Materiały źródłowe

• #1 Leukemia: Symptoms, Signs, Causes, Types & Treatment

  https://my.clevelandclinic.org/health/diseases/4365-leukemia

  Leukemia starts when the DNA of a single cell in your bone marrow changes (mutates) and cant develop and function normally. […] Leukemia is a cancer of the blood, characterized by the rapid growth of abnormal blood cells. This uncontrolled growth takes place in your bone marrow, where most of your bodys blood is made. […] However, if you have leukemia, one of the developing blood cells begins to multiply out of control. These abnormal cells called leukemia cells begin to take over the space inside of your bone marrow. […] Leukemia starts when the DNA of a single cell in your bone marrow changes (mutates). DNA is the instruction code that tells a cell when to grow, how to develop and when to die. Because of the mutation, or coding error, leukemia cells keep multiplying. All cells arising from the original mutated cell also have the mutated DNA. […] Scientists dont know what causes these developing cells to mutate. Theyve been able to identify some common mutations that people diagnosed with different types of leukemia share.

• #2 Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560490/

  Leukemia is a heterogeneous group of hematologic malignancies that arise from the dysfunctional proliferation of developing leukocytes. […] Multiple genetic and environmental risk factors are identified in the development of leukemia. […] The production of abnormal leukocytes defines leukemia as either a primary or secondary process. […] Many genetic risk factors have been identified, such as Klinefelter and Down syndromes, ataxia telangiectasia, Bloom syndrome, and telomeropathies such as Fanconi anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome; germline mutations in RUNX1, CEBPA, to name a few. […] In acute leukemias, these malignant cells are generally immature, poorly differentiated, abnormal leukocytes (blasts) that can either be lymphoblasts or myeloblasts. […] In ALL, chromosomal translocation or abnormal chromosome numbers can lead to mutations in precursor lymphoid cells leading to lymphoblasts.

• #3 Acute myeloid leukemia: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-acute-myeloid-leukemia

  Acute myeloid leukemia (AML) develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. These changes alter normal hematopoietic growth and differentiation, resulting in an accumulation of large numbers of abnormal, immature myeloid cells in the bone marrow and peripheral blood. […] This topic reviews the pathogenesis of AML.

• #4 Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560490/

  Leukemia is a heterogeneous group of hematologic malignancies that arise from the dysfunctional proliferation of developing leukocytes. […] Multiple genetic and environmental risk factors are identified in the development of leukemia. […] The production of abnormal leukocytes defines leukemia as either a primary or secondary process. […] Many genetic risk factors have been identified, such as Klinefelter and Down syndromes, ataxia telangiectasia, Bloom syndrome, and telomeropathies such as Fanconi anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome; germline mutations in RUNX1, CEBPA, to name a few. […] In acute leukemias, these malignant cells are generally immature, poorly differentiated, abnormal leukocytes (blasts) that can either be lymphoblasts or myeloblasts. […] In ALL, chromosomal translocation or abnormal chromosome numbers can lead to mutations in precursor lymphoid cells leading to lymphoblasts.

• #5 Leukemia – Wikipedia

  https://en.wikipedia.org/wiki/Leukemia

  The exact cause of leukemia is unknown. A combination of genetic factors and environmental (non-inherited) factors are believed to play a role. […] Studies in 2009 and 2010 have shown a positive correlation between exposure to formaldehyde and the development of leukemia, particularly myeloid leukemia. […] Among adults, the known causes are natural and artificial ionizing radiation and petrochemicals, notably benzene and alkylating chemotherapy agents for previous malignancies. […] Certain mutations can trigger leukemia by activating oncogenes or deactivating tumor suppressor genes, and thereby disrupting the regulation of cell death, differentiation or division. […] Chronic myelogenous leukemia is associated with a genetic abnormality called the Philadelphia translocation; 95% of people with CML carry the Philadelphia mutation, although this is not exclusive to CML and can be observed in people with other types of leukemia.

• #6 Leukemia – Hematology.org

  https://www.hematology.org/education/patients/blood-cancers/leukemia

  Leukemia is a type of cancer found in your blood and bone marrow and is caused by the rapid production of abnormal white blood cells. […] These abnormal white blood cells are not able to fight infection and impair the ability of the bone marrow to produce red blood cells and platelets. […] Although experts are uncertain about the causes of leukemia, they have identified several risk factors that include the following: Exposure to high levels of radiation, Repeated exposure to certain chemicals (for example, benzene), Chemotherapy, Down Syndrome, A strong family history of leukemia. […] Treatment depends on your age, general health, and type of leukemia. […] Patients with acute leukemia often undergo chemotherapy because this type of treatment targets fast-dividing cells. […] On the other hand, because the cells divide more slowly in chronic leukemia, it is better treated with targeted therapies that attack slowly dividing cells as opposed to traditional chemotherapy that targets rapidly dividing cells. […] Because the cause of leukemia remains unknown, there is no certain way to prevent it.

• #7 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  Acute myeloid leukemia (AML) is a heterogeneous hematopoietic neoplasm which results in clonal proliferation of abnormally differentiated hematopoietic cells. In this review, mechanisms contributing to myeloid leukemogenesis are summarized, highlighting aberrations of epigenetics, transcription factors, signal transduction, cell cycling, and the bone marrow microenvironment. […] The mechanisms contributing to AML are detailed to spotlight recent findings that convey clinical impact. […] Understanding leukemogenesis requires an appreciation of two concepts the function of proteins of commonly mutated genes and how the relevant genes are expressed. […] It is widely recognized that the evolution of AML is unlikely to represent the result of a single biological aberration but instead the consequence of multiple and synergistic aberrations in epigenetic events, cell cycling, proliferation, signal transduction, and apoptosis.

• #8 Common themes in the pathogenesis of acute myeloid leukemia | Oncogene

  https://www.nature.com/articles/1204642

  The pathogenesis of acute myeloid leukemia is associated with the appearance of oncogenic fusion proteins generated as a consequence of specific chromosome translocations. […] As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators that interfere with the process of myeloid differentiation, determine a stage-specific arrest of maturation and enhance cell survival in a cell-type specific manner. […] The abnormal regulation of transcriptional networks occurs through common mechanisms that include recruitment of aberrant co-repressor complexes, alterations in chromatin remodeling, and disruption of specific subnuclear compartments. […] The identification and analysis of common and specific target genes regulated by AML fusion proteins will be of fundamental importance for the full understanding of acute myeloid leukemogenesis and for the implementation of disease-specific drug design.

• #9 Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560490/

  In AML, chromosomal translocations, rearrangements, and gain or loss of chromosomes can lead to mutations and abnormal production of myeloblasts. […] Chromosomal abnormalities in hematopoietic stem cells that are precursors to leucocytes are the most common cause of chronic leukemia. […] In CML, mutations mainly affect granulocytes (most commonly the t(9;22) translocation), and in CLL, they primarily affect lymphocytes (especially B lymphocytes).

• #10 Common themes in the pathogenesis of acute myeloid leukemia | Oncogene

  https://www.nature.com/articles/1204642

  The pathogenesis of acute myeloid leukemia is associated with the appearance of oncogenic fusion proteins generated as a consequence of specific chromosome translocations. […] As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators that interfere with the process of myeloid differentiation, determine a stage-specific arrest of maturation and enhance cell survival in a cell-type specific manner. […] The abnormal regulation of transcriptional networks occurs through common mechanisms that include recruitment of aberrant co-repressor complexes, alterations in chromatin remodeling, and disruption of specific subnuclear compartments. […] The identification and analysis of common and specific target genes regulated by AML fusion proteins will be of fundamental importance for the full understanding of acute myeloid leukemogenesis and for the implementation of disease-specific drug design.

• #11 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Chronic-Myelogenous-Leukemia-Pathogenesis.aspx

  CML was initially differentiated from other types of leukemia by the presence of a genetic abnormality of chromosome 22 in CML cells. […] The shortened chromosome 22 was named the Philadelphia chromosome and is also called the Ph chromosome. […] The translocation of chromosome 9 and chromosome 22 is found only in CML cells. […] This abnormal BCR-ABL gene produces an abnormal protein called Bcr-Abl tyrosine kinase. This BCR-ABL TK leads to the abnormal growth and survival of the cancer cells.

• #12 What Is Cancer? – NCI

  https://www.cancer.gov/about-cancer/understanding/what-is-cancer

  The genetic changes that contribute to cancer tend to affect three main types of genes: proto-oncogenes, tumor suppressor genes, and DNA repair genes. These changes are sometimes called drivers of cancer. […] Proto-oncogenes are involved in normal cell growth and division. However, when these genes are altered in certain ways or are more active than normal, they may become cancer-causing genes (or oncogenes), allowing cells to grow and survive when they should not. […] Tumor suppressor genes are also involved in controlling cell growth and division. Cells with certain alterations in tumor suppressor genes may divide in an uncontrolled manner. […] DNA repair genes are involved in fixing damaged DNA. Cells with mutations in these genes tend to develop additional mutations in other genes and changes in their chromosomes, such as duplications and deletions of chromosome parts. Together, these mutations may cause the cells to become cancerous.

• #13 Pathogenesis of TP53-mutated Acute Myeloid leukemia | Laboratory of Daniel C. Link, M.D. | Washington University in St. Louis

  https://linklab.wustl.edu/pathogenesis-of-tp53/

  The long-term goal of this project is to identify genetic and epigenetic alterations that contribute to the development of treatment-related acute myeloid leukemia (tAML) and to exploit this knowledge to develop new therapies for this high-risk subset of AML. […] Mutations of TP53 are enriched in tAML compared to de novo AML with a frequency of 30-40% and 5-10%, respectively. […] Mutations of TP53 are associated with a complex karyotype and very poor overall survival, both for de novo and tAML cases. […] Our recent studies show that in a subset of tAML, mutations of TP53 are the initiating mutation. […] We hypothesize that both cell-intrinsic events and cell-extrinsic stressors contribute to the development of clonal hematopoiesis. We further hypothesize that repeated genotoxic or hematopoietic stress is key to clonal evolution from clonal hematopoiesis to AML.

• #14 Acute Myeloid Leukemia: From Molecular Pathogenesis to Oral Targeted Therapies

  https://www.uspharmacist.com/article/acute-myeloid-leukemia-from-molecular-pathogenesis-to-oral-targeted-therapies

  Studies using cytogenetic analysis showed that recurrent chromosomal structural variations (karyotype) are characterized by acquired genetic abnormalities (i.e., somatic mutations) that have essential roles in the pathogenesis of leukemia (leukemogenesis). […] Recently, the discovery of molecular and/or genetic alterations has led to the refinement of prognostication in AML. […] Targeted DNA sequencing has identified recurrent mutations in FLT3, NPM1, KIT, CEBPA, and TET2. […] These genes normally participate in normal myeloid cell differentiation and self-renewal. When these genes are altered, they may contribute to leukemogenesis. […] Genes that are commonly involved in epigenetic regulation of myeloid cell differentiation (e.g., DNMT3A, ASXL1, IDH2, and TET2) are also present in preleukemic hematopoietic stem cells and occur early in the evolution of AML.

• #15 What Causes Acute Myeloid Leukemia (AML)? | American Cancer Society

  https://www.cancer.org/cancer/types/acute-myeloid-leukemia/causes-risks-prevention/what-causes.html

  Some genes normally help control when our cells grow, divide to make new cells, or repair mistakes in DNA, or they cause cells to die when theyre supposed to. If these genes arent working properly, it can lead to cells growing out of control. […] Any of these types of DNA changes might lead to cells growing out of control, which might lead to cancer, including AML. For instance, changes in certain genes such as FLT3, c-KIT, and RAS are common in AML cells. These types of changes can stop bone marrow cells from maturing the way they normally would, or help the cells grow out of control. […] Mutations in many different genes can be found in AML cells, but larger changes in one or more chromosomes are also common. Even though these changes involve larger pieces of DNA, their effects are still likely to be due to changes in just one or a few genes that are on that part of the chromosome. Several types of chromosome changes might be found in AML cells:

• #16 Acute Myeloid Leukemia: From Molecular Pathogenesis to Oral Targeted Therapies

  https://www.uspharmacist.com/article/acute-myeloid-leukemia-from-molecular-pathogenesis-to-oral-targeted-therapies

  Acute myeloid leukemia (AML) represents a heterogeneous group of acute hematologic malignancies produced by the myeloid lineage within the hematopoietic system. […] Recent advances in molecular genetics have led to the discovery of new oncogenic signaling pathways and molecular or genetic aberrations involved in the malignant transformation of myeloid precursors to leukemic blasts, which in turn has led to improved diagnostic and therapeutic strategies for patients with AML. […] AML is a clonal disease characterized by the presence of a variety of genetic alterations. Most cases of AML are distinguished by clonal heterogeneity at the time of diagnosis, with the presence of a founding clone and at least one subclone. […] Various patterns of clonal evolution (presence of additional genetic abnormalities in leukemic blasts) at relapse probably contribute to resistance to therapy.

• #17 Editorial for the Special Issue “Molecular Mechanism of Leukemia”

  https://www.mdpi.com/1422-0067/24/18/13936

  Hematopoiesis is the intricate process responsible for all blood cell formation and maintenance, and is tightly regulated by a myriad of intrinsic and extrinsic factors. […] Nonetheless, the fragile balance of normal hematopoiesis often succumbs to a spectrum of genetic and epigenetic aberrations. […] At the core of comprehending leukemia pathogenesis lies the precise unraveling of the roles played by genetic and epigenetic regulatory mechanisms. […] Genetic alterations have the potential to drive neoplasia through oncogene activation or tumor suppressor gene inactivation, while epigenetic modifications can orchestrate changes in gene expression patterns without affecting the genome sequences. […] The intricate interplay of these regulatory processes is paramount in shaping both normal and malignant hematopoiesis.

• #18 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  The diverse mechanisms culminating in AML support the notion of a distinctly heterogeneous disease that extends beyond prior and current classifications. […] Recent years have witnessed dramatic developments in molecular biology, genomics, the understanding of the role of the bone marrow microenvironment, as well as their corresponding effects on leukemogenesis. […] Loss of DNMT activity results in altered methylation patterns, culminating in aberrations of critical regulators of HSC differentiation, such as PU.1, IKAROS, and RUNX1 impairing terminal differentiation and leading to AML. […] Aberrant TET2 is present in up to 24% of myeloid neoplasms, including primary myelofibrosis, chronic myelomonocytic leukemia, MDS, and AML. […] The leukemogenic mechanism appears to be enhancement of HSC self-renewal through aberrant methylation associated with loss of functional TET2.

• #19 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  The diverse mechanisms culminating in AML support the notion of a distinctly heterogeneous disease that extends beyond prior and current classifications. […] Recent years have witnessed dramatic developments in molecular biology, genomics, the understanding of the role of the bone marrow microenvironment, as well as their corresponding effects on leukemogenesis. […] Loss of DNMT activity results in altered methylation patterns, culminating in aberrations of critical regulators of HSC differentiation, such as PU.1, IKAROS, and RUNX1 impairing terminal differentiation and leading to AML. […] Aberrant TET2 is present in up to 24% of myeloid neoplasms, including primary myelofibrosis, chronic myelomonocytic leukemia, MDS, and AML. […] The leukemogenic mechanism appears to be enhancement of HSC self-renewal through aberrant methylation associated with loss of functional TET2.

• #20 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  The mixed-lineage leukemia gene (MLL, also known as KMT2A) encodes for a histone methyltransferase that acts as a master regulator of gene expression during hematopoiesis, and whose protein product controls the HOX gene family. […] MLL rearrangements are found in approximately 10% of myeloid leukemias and are more common in secondary or therapy-related leukemias, particularly after agents that target topoisomerase II. […] ASXL1 mutations promote HSC aberrations while maintaining survival, creating a predisposition to leukemic transformation by cooperating with the acquisition of mutant RUNX1, MLL, NRAS, or loss-of-function of TET2. […] The role of additional sex combs like 1 (ASXL1) in hematopoiesis and leukemogenesis has yet to be fully elucidated. […] The CCAAT-enhancer binding protein alpha (CEBP) is a transcription factor that regulates differentiation and proliferation in myeloid progenitors.

• #21 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  The mixed-lineage leukemia gene (MLL, also known as KMT2A) encodes for a histone methyltransferase that acts as a master regulator of gene expression during hematopoiesis, and whose protein product controls the HOX gene family. […] MLL rearrangements are found in approximately 10% of myeloid leukemias and are more common in secondary or therapy-related leukemias, particularly after agents that target topoisomerase II. […] ASXL1 mutations promote HSC aberrations while maintaining survival, creating a predisposition to leukemic transformation by cooperating with the acquisition of mutant RUNX1, MLL, NRAS, or loss-of-function of TET2. […] The role of additional sex combs like 1 (ASXL1) in hematopoiesis and leukemogenesis has yet to be fully elucidated. […] The CCAAT-enhancer binding protein alpha (CEBP) is a transcription factor that regulates differentiation and proliferation in myeloid progenitors.

• #22

  https://journals.lww.com/oncology-times/fulltext/2021/08050/mechanism_of_leukemia_pathogenesis___possible.2.aspx

  In a new research paper, scientists from Northwestern University School of Medicine in Chicago, describe how molecular mechanisms of the ASXL1 gene mutation are involved in leukemia pathogenesis, and they also identify a possible targeted therapy for myeloid cancers. […] The researchers showed how truncated ASXL1 increases BAP1 protein stability, enhances BAP1 recruitment to chromatin, and promotes the expression of a pro-leukemic transcriptional signature. […] ASXL1 is the most frequently mutated gene in myeloid cancers, including leukemia. […] It was basically established in the literature that the mutation of ASXL1 resulted in degradation, and that there’s a loss of function. We actually demonstrated that it is a gain of function and inhibition of the hyperactivated enzyme can be therapeutic.

• #23 Acute Myeloid Leukemia: From Molecular Pathogenesis to Oral Targeted Therapies

  https://www.uspharmacist.com/article/acute-myeloid-leukemia-from-molecular-pathogenesis-to-oral-targeted-therapies

  IDH1 or IDH2 mutations tend to be mutually exclusive and confer a neomorphic enzymatic activity, resulting in the reduction of alpha-ketoglutarate to the oncometabolite 2-hydroxyglutarate and leading to epigenetic alterations and impaired hematopoietic differentiation. […] Ultimately, as researchers gain insight into the genetic and epigenetic changes relevant to the pathogenesis of AML, the identification of novel molecular and genetic markers will contribute to an understanding of leukemias biology, leading to improvements in patient risk assessment and the eventual development of novel therapies targeting these molecular or genetic changes.

• #24 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  In mutated CEBPA, which occurs in up to 14% of AML, the synthesis of the 42 kDa protein is impaired and the expression of the 30 kDa protein is preserved, conferring a differentiation block during myeloid maturation. […] Nucleophosmin (NPM1) is a multifunctional nucleocytoplasmic shuttling phosphoprotein that is found primarily in the nucleolus. […] In the absence of a partnered gene fusion, it is thought that NPM1mut exerts its leukemogenic effect through aberrant shuttling function, since mutations in NPM1 appear to increase the concentration of the aberrant protein in the cytoplasm and decrease its concentration in the nucleus. […] The rat sarcoma (RAS) proteins are signal transducers that relay to downstream targets to regulate cell proliferation. […] Among the most common activating signaling mutations in AML are the mutations of FLT3.

• #25 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  The ultimate consequence of persistent RAS signaling is an increased sensitivity to GM-CSF and a skewing of the development of the hematopoietic stem cell toward the common myeloid and granulocyte-macrophage progenitor, producing a strong proliferative advantage. […] In AML, there are two common constitutively activating FLT3 mutations: an internal tandem duplication (ITD) and a tyrosine kinase domain (TKD) mutation. […] The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy. […] The bone marrow architecture is characterized by specialized stem cell niches at the perivascular and endosteal sites of the intramedullary space, where the bulk of HSCs are found.

• #26 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  The ultimate consequence of persistent RAS signaling is an increased sensitivity to GM-CSF and a skewing of the development of the hematopoietic stem cell toward the common myeloid and granulocyte-macrophage progenitor, producing a strong proliferative advantage. […] In AML, there are two common constitutively activating FLT3 mutations: an internal tandem duplication (ITD) and a tyrosine kinase domain (TKD) mutation. […] The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy. […] The bone marrow architecture is characterized by specialized stem cell niches at the perivascular and endosteal sites of the intramedullary space, where the bulk of HSCs are found.

• #27 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  The ultimate consequence of persistent RAS signaling is an increased sensitivity to GM-CSF and a skewing of the development of the hematopoietic stem cell toward the common myeloid and granulocyte-macrophage progenitor, producing a strong proliferative advantage. […] In AML, there are two common constitutively activating FLT3 mutations: an internal tandem duplication (ITD) and a tyrosine kinase domain (TKD) mutation. […] The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy. […] The bone marrow architecture is characterized by specialized stem cell niches at the perivascular and endosteal sites of the intramedullary space, where the bulk of HSCs are found.

• #28 Mechanism and novel therapeutic target identified in acute myeloid leukemia – Oncology Central

  https://www.oncology-central.com/mechanism-and-novel-therapeutic-target-identified-in-acute-myeloid-leukemia/

  Researchers at Indiana University (IN, USA) have identified two proteins, termed FAK and PAK1, which are closely associated with the onset and relapse of acute myeloid leukemia. […] The problem is that the majority of patients relapse because they have remaining residual leukemic stem cells in the bone marrow that are resistant to currently available therapies, including chemotherapy, he continued. […] Utilizing animal models, the researchers at Indiana University identified the proteins FAK and PAK1 as key to FLT3- and KIT-driven leukemia development. […] In further experiments in both mice and human cell samples, the team identified several FAK- and PAK1-targeting drugs that produced the same antileukemic effects as eliminating the proteins by knocking out the genes.

• #29 Mechanism and novel therapeutic target identified in acute myeloid leukemia – Oncology Central

  https://www.oncology-central.com/mechanism-and-novel-therapeutic-target-identified-in-acute-myeloid-leukemia/

  Researchers at Indiana University (IN, USA) have identified two proteins, termed FAK and PAK1, which are closely associated with the onset and relapse of acute myeloid leukemia. […] The problem is that the majority of patients relapse because they have remaining residual leukemic stem cells in the bone marrow that are resistant to currently available therapies, including chemotherapy, he continued. […] Utilizing animal models, the researchers at Indiana University identified the proteins FAK and PAK1 as key to FLT3- and KIT-driven leukemia development. […] In further experiments in both mice and human cell samples, the team identified several FAK- and PAK1-targeting drugs that produced the same antileukemic effects as eliminating the proteins by knocking out the genes.

• #30 Acute myeloid leukemia – Wikipedia

  https://en.wikipedia.org/wiki/Acute_myeloid_leukemia

  Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. […] The underlying mechanism involves replacement of normal bone marrow with leukemia cells, which results in a drop in red blood cells, platelets, and normal white blood cells. […] The malignant cell in AML is the myeloblast. In normal development of blood cells (hematopoiesis), the myeloblast is an immature precursor of myeloid white blood cells; a normal myeloblast will mature into a white blood cell such as an eosinophil, basophil, neutrophil or monocyte. In AML, though, a single myeloblast accumulates genetic changes which stop maturation, increase its proliferation, and protect it from programmed cell death (apoptosis).

• #31 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  In mutated CEBPA, which occurs in up to 14% of AML, the synthesis of the 42 kDa protein is impaired and the expression of the 30 kDa protein is preserved, conferring a differentiation block during myeloid maturation. […] Nucleophosmin (NPM1) is a multifunctional nucleocytoplasmic shuttling phosphoprotein that is found primarily in the nucleolus. […] In the absence of a partnered gene fusion, it is thought that NPM1mut exerts its leukemogenic effect through aberrant shuttling function, since mutations in NPM1 appear to increase the concentration of the aberrant protein in the cytoplasm and decrease its concentration in the nucleus. […] The rat sarcoma (RAS) proteins are signal transducers that relay to downstream targets to regulate cell proliferation. […] Among the most common activating signaling mutations in AML are the mutations of FLT3.

• #32 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  In mutated CEBPA, which occurs in up to 14% of AML, the synthesis of the 42 kDa protein is impaired and the expression of the 30 kDa protein is preserved, conferring a differentiation block during myeloid maturation. […] Nucleophosmin (NPM1) is a multifunctional nucleocytoplasmic shuttling phosphoprotein that is found primarily in the nucleolus. […] In the absence of a partnered gene fusion, it is thought that NPM1mut exerts its leukemogenic effect through aberrant shuttling function, since mutations in NPM1 appear to increase the concentration of the aberrant protein in the cytoplasm and decrease its concentration in the nucleus. […] The rat sarcoma (RAS) proteins are signal transducers that relay to downstream targets to regulate cell proliferation. […] Among the most common activating signaling mutations in AML are the mutations of FLT3.

• #33 Acute myeloid leukemia – Wikipedia

  https://en.wikipedia.org/wiki/Acute_myeloid_leukemia

  Much of the diversity and heterogeneity of AML is because leukemic transformation can occur at a number of different steps along the differentiation pathway. […] Specific cytogenetic abnormalities can be found in many people with AML; the types of chromosomal abnormalities often have prognostic significance. […] The clinical signs and symptoms of AML result from the growth of leukemic clone cells, which tends to interfere with the development of normal blood cells in the bone marrow. […] Many cells develop mutations in genes that affect epigenetics, such as DNA methylation. […] Such mutations include in the DNA demethylase TET2 and the metabolic enzymes IDH1 and IDH2, which lead to the generation of a novel oncometabolite, D-2-hydroxyglutarate, which inhibits the activity of epigenetic enzymes such as TET2. […] Epigenetic mutations may lead to the silencing of tumor suppressor genes and/or the activation of proto-oncogenes.

• #34 Scientists discover a new mechanism for therapy resistance in acute leukemias – Children’s Medical Center Research Institute (CRI) | Dallas Texas

  https://cri.utsw.edu/scientists-discover-a-new-mechanism-for-therapy-resistance-in-acute-leukemias/

  The presence of IDH second-site mutations prevents the formation of a stable enzyme-inhibitor complex, restores R-2-HG production, and drives therapy resistance in IDH-mutant AML cells and patients. […] Our new cell models and the discovery of new IDH second-site mutations with acquired resistance will likely have broad implications for understanding the molecular basis of therapy resistance in human cancers.

• #35 Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia | Leukemia

  https://www.nature.com/articles/s41375-023-01963-4

  Because functional changes in splicing regulatory proteins can promote oncogenesis through overexpression, alteration-of-function, and mutations, therapeutic targeting of the spliceosome holds promise as a novel cancer therapy. […] We show that phosphorylation patterns of SR proteins are altered during the development of cytarabine resistance in AML, and that the combination of spliceosome inhibitors and other approved drugs, including the BCL2 inhibitor venetoclax, improves the therapeutic response in cells from patients with AML, even in a background of cytarabine resistance. […] We demonstrate that posttranslational modifications of splicing factors are involved in cytarabine resistance and can be effectively and safely targeted in AML. […] We confirm the overexpression of SRRM2 in a series of patients with myeloid disease, with a particularly significant increase in expression in AML.

• #36 Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia | Leukemia

  https://www.nature.com/articles/s41375-023-01963-4

  Mutations in mRNA splicing genes has been linked to drug resistance development in AML. […] We show by phosphoproteomics and immunohistochemistry that the phosphorylation of SR proteins increases after the development of acquired resistance to cytarabine. […] Our validation in a cohort of 64 patients with AML proves the usefulness of quantifying phospho-SR protein levels as a predictive biomarker of cytarabine response not linked to the presence of specific mutations in the components of the splicing machinery. […] In sum, we demonstrate that altered phosphorylation of SR proteins is related to primary or secondary resistance to cytarabine, and might be useful to predict response.

• #37 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200813/Researchers-identify-new-mechanism-responsible-for-causing-leukemia.aspx

  In a novel step forward, researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) have identified covalently closed circular RNAs (circRNAs) from key genes involved in leukemia development and provided greater understanding of their roles in haematological malignancies. […] The team’s analysis made inroads into understanding the role of circASXL1-1 in leukemia. Their data show that depletion of circASXL1-1 led to decreased H2AK119 ubiquitination (H2AK119ub) and this was through BRCA-1 associated protein 1 (BAP1) activity, a deubiquitinating enzyme and an important epigenetic regulator in leukemia. […] This work has provided insights into a new mechanism for the regulation of H2AK119ub levels in hematopoietic progenitors – via interaction of circASXL1-1 and BAP1. […] The epigenetic signature identified could thus pave the way for future therapeutic developments of „epi-drugs”. […] More importantly, findings from this study will lay the foundation for the development of new RNA-based therapeutics for leukemia.

• #38 Acute myeloid leukemia – Wikipedia

  https://en.wikipedia.org/wiki/Acute_myeloid_leukemia

  Much of the diversity and heterogeneity of AML is because leukemic transformation can occur at a number of different steps along the differentiation pathway. […] Specific cytogenetic abnormalities can be found in many people with AML; the types of chromosomal abnormalities often have prognostic significance. […] The clinical signs and symptoms of AML result from the growth of leukemic clone cells, which tends to interfere with the development of normal blood cells in the bone marrow. […] Many cells develop mutations in genes that affect epigenetics, such as DNA methylation. […] Such mutations include in the DNA demethylase TET2 and the metabolic enzymes IDH1 and IDH2, which lead to the generation of a novel oncometabolite, D-2-hydroxyglutarate, which inhibits the activity of epigenetic enzymes such as TET2. […] Epigenetic mutations may lead to the silencing of tumor suppressor genes and/or the activation of proto-oncogenes.

• #39 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

  https://www.intechopen.com/chapters/44045

  The Acute lymphoblastic leukemia (ALL), it produced as a result of a process of malignant transformation of a progenitor lymphocytic cell in the B and T lineages. In ALL, the majority of the cases, the transformation affects the B lineage cells. […] The molecular alterations that are required for the development of a malignant disease is a rare phenomenon when one considers the large number of target cells susceptible to this condition, in other words, a single genetic change rarely be sufficient for developing a malignant tumor. This means that a small percentage of people (1%) who develop malignant hematological disease, probably only 1 cell mutated in a critical gene for the proliferation, differentiation and survival of progenitor cells. There is evidence supporting a sequential multistep process, of alterations in several oncogenes in tumor suppressor genes or microRNA genes in cancerigen cells.

• #40 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

  https://www.intechopen.com/chapters/44045

  The Acute lymphoblastic leukemia (ALL), it produced as a result of a process of malignant transformation of a progenitor lymphocytic cell in the B and T lineages. In ALL, the majority of the cases, the transformation affects the B lineage cells. […] The molecular alterations that are required for the development of a malignant disease is a rare phenomenon when one considers the large number of target cells susceptible to this condition, in other words, a single genetic change rarely be sufficient for developing a malignant tumor. This means that a small percentage of people (1%) who develop malignant hematological disease, probably only 1 cell mutated in a critical gene for the proliferation, differentiation and survival of progenitor cells. There is evidence supporting a sequential multistep process, of alterations in several oncogenes in tumor suppressor genes or microRNA genes in cancerigen cells.

• #41 Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560490/

  Leukemia is a heterogeneous group of hematologic malignancies that arise from the dysfunctional proliferation of developing leukocytes. […] Multiple genetic and environmental risk factors are identified in the development of leukemia. […] The production of abnormal leukocytes defines leukemia as either a primary or secondary process. […] Many genetic risk factors have been identified, such as Klinefelter and Down syndromes, ataxia telangiectasia, Bloom syndrome, and telomeropathies such as Fanconi anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome; germline mutations in RUNX1, CEBPA, to name a few. […] In acute leukemias, these malignant cells are generally immature, poorly differentiated, abnormal leukocytes (blasts) that can either be lymphoblasts or myeloblasts. […] In ALL, chromosomal translocation or abnormal chromosome numbers can lead to mutations in precursor lymphoid cells leading to lymphoblasts.

• #42 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

  https://www.intechopen.com/chapters/44045

  The ALL of T-cell type represents about 10% to 15% of the ALL in adults and the 25% in children and their clinical behavior is the most aggressive, the patients have a higher percentage of failure of remission induction, relapse rate is also higher, and had infiltration at central nervous system compared with B-cell ALL. In this sense, is known that the oncogenes and tumor suppressor genes are implicated in ALL-T are: c-MYC, NOTCH, LMO1 / 2, LYL1, TAL1 / 2, Hox11 and HOX11L2. It is clear that NOTCH activated is able to induce leukemogenesis of T cell and this is critical for the progression to ALL-T. […] The key features in the pathophysiology of the ALL is its monoclonal origin, uncontrolled cell proliferation by sustained self-stimulation of their receptors for growth, no response to inhibitory signals, and cellular longevity conditioned by decreased apoptosis.

• #43 Scientists discover a unique mechanism for a high-risk leukemia – St. Jude Children’s Research Hospital

  https://www.stjude.org/media-resources/news-releases/2016-medicine-science-news/scientists-discover-a-unique-mechanism-for-a-high-risk-leukemia.html

  Genomic analysis revealed the details of four distinctly different chromosomal rearrangements in the leukemia. All resulted in a truncated version of a gene called the erythropoietin receptor (EPOR) gene, and all produced the same outcome—driving the white blood cells to proliferate out of control. […] To our knowledge, this is a previously unknown mechanism for leukemia, Mullighan said. […] In analysis of cells from patients with ALL, Iacobucci found the characteristic rearrangements in all the leukemic cells, suggesting these changes were fundamental to the development of cancer. […] Importantly, Iacobucci and collaborators found the chromosomal alterations arise early in the development of the leukemia and persist as the disease progresses. […] That finding was important because it suggests that treatments for this leukemia targeting this receptor wont just impact a subset of the leukemia cells, allowing others to keep proliferating, Iacobucci said.

• #44 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

  https://www.intechopen.com/chapters/44045

  The ALL of T-cell type represents about 10% to 15% of the ALL in adults and the 25% in children and their clinical behavior is the most aggressive, the patients have a higher percentage of failure of remission induction, relapse rate is also higher, and had infiltration at central nervous system compared with B-cell ALL. In this sense, is known that the oncogenes and tumor suppressor genes are implicated in ALL-T are: c-MYC, NOTCH, LMO1 / 2, LYL1, TAL1 / 2, Hox11 and HOX11L2. It is clear that NOTCH activated is able to induce leukemogenesis of T cell and this is critical for the progression to ALL-T. […] The key features in the pathophysiology of the ALL is its monoclonal origin, uncontrolled cell proliferation by sustained self-stimulation of their receptors for growth, no response to inhibitory signals, and cellular longevity conditioned by decreased apoptosis.

• #45 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Chronic-Myelogenous-Leukemia-Pathogenesis.aspx

  Leukemia is the cancer of the cells within the bone marrow and those in blood. Here the stem cells of the bone marrow that produce cells of the blood including red blood cells, white blood cells or platelets, multiply uncontrollably. […] CML is caused by change or a mutation in the DNA of a single cell in the bone marrow. This mutation is acquired after birth and is not hereditary or inherited from parents. […] Normally cells with a mutated DNA are killed off by the mechanism within the cell. Sometimes this programmed death of the damaged cell fails to occur and this results in crowding out of the normal cells. […] There is an uncontrolled growth of CML cells in the marrow. The precursor cells of the red blood cells and platelets are usually not affected but those of white blood cells may be affected.

• #46 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Chronic-Myelogenous-Leukemia-Pathogenesis.aspx

  CML was initially differentiated from other types of leukemia by the presence of a genetic abnormality of chromosome 22 in CML cells. […] The shortened chromosome 22 was named the Philadelphia chromosome and is also called the Ph chromosome. […] The translocation of chromosome 9 and chromosome 22 is found only in CML cells. […] This abnormal BCR-ABL gene produces an abnormal protein called Bcr-Abl tyrosine kinase. This BCR-ABL TK leads to the abnormal growth and survival of the cancer cells.

• #47 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Chronic-Myelogenous-Leukemia-Pathogenesis.aspx

  CML was initially differentiated from other types of leukemia by the presence of a genetic abnormality of chromosome 22 in CML cells. […] The shortened chromosome 22 was named the Philadelphia chromosome and is also called the Ph chromosome. […] The translocation of chromosome 9 and chromosome 22 is found only in CML cells. […] This abnormal BCR-ABL gene produces an abnormal protein called Bcr-Abl tyrosine kinase. This BCR-ABL TK leads to the abnormal growth and survival of the cancer cells.

• #48 Mechanism of a Medication for Chronic Myeloid Leukemia

  https://www.biointeractive.org/classroom-resources/mechanism-medication-chronic-myeloid-leukemia

  This animation shows how the cancer treatment Gleevec inhibits the cancer-causing protein BCR-ABL. […] Gleevec is a drug for treating chronic myeloid leukemia (CML), a cancer of white blood cells. In CML, white blood cells divide uncontrollably due to an overactive mutant tyrosine kinase protein called BCR-ABL. Gleevec is designed to specifically bind to and inactivate BCR-ABL, which prevents it from signaling the division of more white blood cells.

• #49 Mechanism of a Medication for Chronic Myeloid Leukemia

  https://www.biointeractive.org/classroom-resources/mechanism-medication-chronic-myeloid-leukemia

  This animation shows how the cancer treatment Gleevec inhibits the cancer-causing protein BCR-ABL. […] Gleevec is a drug for treating chronic myeloid leukemia (CML), a cancer of white blood cells. In CML, white blood cells divide uncontrollably due to an overactive mutant tyrosine kinase protein called BCR-ABL. Gleevec is designed to specifically bind to and inactivate BCR-ABL, which prevents it from signaling the division of more white blood cells.

• #50

  https://www.jci.org/articles/view/64101/citations

  Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Here, we highlight important genetic alterations that contribute to tumorigenesis, clinical progression, and chemorefractoriness of CLL. […] All CLLs share a common gene expression profile that suggests derivation from antigen-experienced B cells, a model supported by frequent B cell receptor repertoire skewing and stereotypy. […] Many CLL patients carry mutated immunoglobulin heavy-chain variable genes, while approximately 35% harbor unmutated IgV genes, which are associated with an inferior outcome. […] Deletion of chromosome 13q14, which is the most common genetic mutation at diagnosis, is considered an initiating lesion that frequently results in disruption of the tumor suppressor locus DLEU2/MIR15A/MIR16A. […] Next-generation sequencing has revealed additional recurrent genetic lesions that are implicated in CLL pathogenesis. […] These advancements in the molecular genetics of CLL have important implications for stratifying treatment based on molecular prognosticators and for targeted therapy.

• #51

  https://www.jci.org/articles/view/64101/citations

  Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Here, we highlight important genetic alterations that contribute to tumorigenesis, clinical progression, and chemorefractoriness of CLL. […] All CLLs share a common gene expression profile that suggests derivation from antigen-experienced B cells, a model supported by frequent B cell receptor repertoire skewing and stereotypy. […] Many CLL patients carry mutated immunoglobulin heavy-chain variable genes, while approximately 35% harbor unmutated IgV genes, which are associated with an inferior outcome. […] Deletion of chromosome 13q14, which is the most common genetic mutation at diagnosis, is considered an initiating lesion that frequently results in disruption of the tumor suppressor locus DLEU2/MIR15A/MIR16A. […] Next-generation sequencing has revealed additional recurrent genetic lesions that are implicated in CLL pathogenesis. […] These advancements in the molecular genetics of CLL have important implications for stratifying treatment based on molecular prognosticators and for targeted therapy.

• #52

  https://www.jci.org/articles/view/64101/citations

  Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Here, we highlight important genetic alterations that contribute to tumorigenesis, clinical progression, and chemorefractoriness of CLL. […] All CLLs share a common gene expression profile that suggests derivation from antigen-experienced B cells, a model supported by frequent B cell receptor repertoire skewing and stereotypy. […] Many CLL patients carry mutated immunoglobulin heavy-chain variable genes, while approximately 35% harbor unmutated IgV genes, which are associated with an inferior outcome. […] Deletion of chromosome 13q14, which is the most common genetic mutation at diagnosis, is considered an initiating lesion that frequently results in disruption of the tumor suppressor locus DLEU2/MIR15A/MIR16A. […] Next-generation sequencing has revealed additional recurrent genetic lesions that are implicated in CLL pathogenesis. […] These advancements in the molecular genetics of CLL have important implications for stratifying treatment based on molecular prognosticators and for targeted therapy.

• #53

  https://www.jci.org/articles/view/64101/citations

  Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Here, we highlight important genetic alterations that contribute to tumorigenesis, clinical progression, and chemorefractoriness of CLL. […] All CLLs share a common gene expression profile that suggests derivation from antigen-experienced B cells, a model supported by frequent B cell receptor repertoire skewing and stereotypy. […] Many CLL patients carry mutated immunoglobulin heavy-chain variable genes, while approximately 35% harbor unmutated IgV genes, which are associated with an inferior outcome. […] Deletion of chromosome 13q14, which is the most common genetic mutation at diagnosis, is considered an initiating lesion that frequently results in disruption of the tumor suppressor locus DLEU2/MIR15A/MIR16A. […] Next-generation sequencing has revealed additional recurrent genetic lesions that are implicated in CLL pathogenesis. […] These advancements in the molecular genetics of CLL have important implications for stratifying treatment based on molecular prognosticators and for targeted therapy.

• #54 ATM mutations in chronic lymphocytic leukemia | Karolinska Institutet

  https://news.ki.se/atm-mutations-in-chronic-lymphocytic-leukemia

  In chronic lymphocytic leukemia (CLL), certain recurrent genetic alterations are known to influence disease progression and survival. One important abnormality is the loss of part of chromosome 11, del(11q), which is associated with a more aggressive disease course. […] ATM mutations were identified in approximately 7 per cent of patients and frequently co-occurred with del(11q). […] Furthermore, patients with any ATM-related abnormalities (ATM mutations and/or del(11q)) experienced a significantly shorter TTFT. However, after adjusting for other genetic factors, only del(11q) and not ATM mutations alone emerged as an independent predictor of earlier need for treatment. […] In short, our findings strengthen the role of del(11q) and not ATM mutations alone as a critical marker for higher risk of progression in patients with CLL.

• #55 Duvelisib Plus Venetoclax Is Active in Relapsed/Refractory CLL and Richter Syndrome

  https://www.onclive.com/view/duvelisib-plus-venetoclax-is-active-in-relapsed-refractory-cll-and-richter-syndrome

  Duvelisib plus venetoclax was shown to be active in relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter syndrome (RS), including in patients with high-risk, TP53-aberrant disease and those who had received prior treatment with BTK inhibitors, according to data from the phase 2 portion of a phase 1/2 trial (NCT03534323) that were presented at the 2024 ASH Annual Meeting. […] The all-oral, minimal residual disease [MRD]driven, time-limited regimen duvelisib plus venetoclax is active in relapsed/refractory CLL and RS, including in high-risk patients with TP53-aberrant disease and [those who received treatment] post-BTK inhibitor, lead study author Jennifer L. Crombie, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, said during a presentation of the data. […] Our data support exploration of duvelisib plus venetoclax in larger studies of patients with relapsed/refractory CLL and RS, Crombie concluded during the presentation.

• #56 Bone marrow stromal cells in the pathogenesis of acute myeloid leukemia

  https://www.imrpress.com/journal/FBL/19/1/10.2741/4203

  Acute myeloid leukemia (AML) is clonal disorder affecting pluripotent stem cell and characterized by ineffective hematopoiesis. Genetic abnormalities in a progenitor cells is thought to lead to uncontrolled growth of leukemia cells. […] In addition, in the last years, it has been clearly recognized that the hematopoietic microenvironment (HM) plays an important role in the pathogenesis of AML. The HM can regulate hematopoiesis by interacting directly with HC and/or by secreting regulatory molecules that exert a positive or negative influence on the growth of HC. […] Several studies propose that important quantitative and functional alterations are present in the BMSC of AML patients. AML may arise in the setting of an abnormal HM, resulting in the generation of multiple populations with varying initiation event. Dysfunction of HM may contribute to leukemia by supplying abundant growth factors that promote proliferation and/or inhibit apoptosis. Recent discoveries utilizing mouse models showed that genetic alteration in cells of HM can induce AML.

• #57 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  The ultimate consequence of persistent RAS signaling is an increased sensitivity to GM-CSF and a skewing of the development of the hematopoietic stem cell toward the common myeloid and granulocyte-macrophage progenitor, producing a strong proliferative advantage. […] In AML, there are two common constitutively activating FLT3 mutations: an internal tandem duplication (ITD) and a tyrosine kinase domain (TKD) mutation. […] The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy. […] The bone marrow architecture is characterized by specialized stem cell niches at the perivascular and endosteal sites of the intramedullary space, where the bulk of HSCs are found.

• #58 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  In a more general sense, it is recognized that residual leukemic stem cells (LSCs) residing in the bone marrow represent a major determinant of treatment failure and lead to early relapse. […] The interaction between programmed cell death-1 (PD-1) and its ligand (PD-L1) functions as an immune checkpoint to promote self-tolerance through suppression of T-cell inflammatory activity. […] The numerous paths that lead to the genesis of leukemia are frequently intertwined, and cooperating mutations involving epigenetic regulators, oncoproteins, transcription factors, tumor suppressors, and activating signaling mutations contribute to the enormous complexity of leukemogenesis.

• #59 The role of LSCs in the pathogenesis and progression of leukemia & strategies to target LSCs | VJHemOnc

  https://www.vjhemonc.com/video/fbs33im25c4-the-role-of-lscs-in-the-pathogenesis-and-progression-of-leukemia-strategies-to-target-lscs/

  Andreas Trumpp, PhD, German Cancer Research Center, Heidelberg, Germany, comments on the role of leukemic stem cells (LSCs) in the development of leukemias including acute and chronic myeloid leukemia, highlighting how they can also lead to relapse and resistance to treatment, and discussing strategies to target those LSCs. […] This interview took place at the 24th Annual John Goldman Conference on Chronic Myeloid Leukemia (ESH CML) held in Mandelieu-La Napoule, France.

• #60 Leukemia Mediated Endothelial Cell Activation Modulates Leukemia Cell Susceptibility to Chemotherapy through a Positive Feedback Loop Mechanism | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060823

  In acute myeloid leukemia (AML), the chances of achieving disease-free survival are low. […] We demonstrate that leukemia cells themselves initiate these interactions by directly modulating the behavior of resting ECs through the induction of EC activation. […] The ability of adherent cells to later detach and again become proliferative following exposure to chemotherapy suggests a role of this process in relapse. […] Finally, because leukemia cells themselves induce EC activation, we postulate a positive-feedback loop in leukemia that exists to support the growth and relapse of the disease. […] These findings indicate an intimate relationship between ECs and leukemia, wherein leukemia cells are able to significantly alter EC activity. […] Given this response, we hypothesized that leukemia cells alter EC activity, and through this altered activity, ECs produce microenvironments responsible for leukemia growth, survival and, ultimately, relapse.

• #61 Leukemia Mediated Endothelial Cell Activation Modulates Leukemia Cell Susceptibility to Chemotherapy through a Positive Feedback Loop Mechanism | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060823

  Overall, this data implicates EC activation as a new mechanism in leukemia, demonstrates that processes involved in the inflammatory response are active in leukemia and highlights the potential of using anti-inflammatory drugs during standard treatment of the disease. […] Our finding that leukemia cells themselves can activate ECs, and thus initiate this process, is indicative of a positive feedback loop scenario. […] In this loop, leukemia cells produce conditions that activate ECs. […] In this attached state, leukemia cells become quiescent and are protected from standard chemotherapy. […] These bound cells may represent residual cellular mediators of leukemia relapse given our finding that upon release these cells re-enter cell cycle even following Ara-C treatment. […] Overall, a deleterious positive feedback mechanism is established that supports the survival of leukemia. […] The identification of this regulatory mechanism may help identify new therapies for leukemia that aim to disrupt this supportive process.

• #62 Leukemia Mediated Endothelial Cell Activation Modulates Leukemia Cell Susceptibility to Chemotherapy through a Positive Feedback Loop Mechanism | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060823

  Overall, this data implicates EC activation as a new mechanism in leukemia, demonstrates that processes involved in the inflammatory response are active in leukemia and highlights the potential of using anti-inflammatory drugs during standard treatment of the disease. […] Our finding that leukemia cells themselves can activate ECs, and thus initiate this process, is indicative of a positive feedback loop scenario. […] In this loop, leukemia cells produce conditions that activate ECs. […] In this attached state, leukemia cells become quiescent and are protected from standard chemotherapy. […] These bound cells may represent residual cellular mediators of leukemia relapse given our finding that upon release these cells re-enter cell cycle even following Ara-C treatment. […] Overall, a deleterious positive feedback mechanism is established that supports the survival of leukemia. […] The identification of this regulatory mechanism may help identify new therapies for leukemia that aim to disrupt this supportive process.

• #63 Temple Researchers Discover Drug Resistance Mechanism in Leukemia, Identify Novel Treatment Strategy | Temple Health

  https://www.templehealth.org/about/news/temple-researchers-discover-drug-resistance-mechanism-in-leukemia-identify-novel-treatment-strategy

  Leukemia, a cancer of blood-forming tissues, modulates the bone marrow niche to protect and promote the survival of tumor cells. […] This resistance, the researchers discovered, hinges on overexpression of a molecule known as transforming growth factor beta receptor (TGFR) kinase, which is located on the leukemia cell surface. […] Previous research has shown that leukemia cells displaying deficiency of BRCA1 and BRCA2 proteins are sensitive to PARP inhibition while circulating in the blood. […] We discovered that the same leukemia cells are resistant to the inhibitors in the bone marrow microenvironment. […] Examination of factors in the replicated bone marrow microenvironment identified TGF-1 as an important player in resistance. […] TGF-1, a protein generated by stromal cells in the bone marrow niche, activates TGFR kinase.

• #64 Temple Researchers Discover Drug Resistance Mechanism in Leukemia, Identify Novel Treatment Strategy | Temple Health

  https://www.templehealth.org/about/news/temple-researchers-discover-drug-resistance-mechanism-in-leukemia-identify-novel-treatment-strategy

  With TGFR kinase levels noticeably elevated in leukemia cells, the researchers decided to test the effects of TGFR kinase inhibition. […] They observed that treatment with molecules that blocked TGFR kinase activation by TGF-1 not only halted signaling along the TGF-1-TGFR kinase axis but also rendered cells sensitive to PARP inhibitors. […] Weve now discovered a central and constitutive mechanism underlying PARP drug resistance in leukemia, Dr. Skorski said. […] And we went a step further, showing that resistance can be overcome through a therapeutic strategy that combines inhibitors targeting PARP and TGFR kinase.

• #65 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  In a more general sense, it is recognized that residual leukemic stem cells (LSCs) residing in the bone marrow represent a major determinant of treatment failure and lead to early relapse. […] The interaction between programmed cell death-1 (PD-1) and its ligand (PD-L1) functions as an immune checkpoint to promote self-tolerance through suppression of T-cell inflammatory activity. […] The numerous paths that lead to the genesis of leukemia are frequently intertwined, and cooperating mutations involving epigenetic regulators, oncoproteins, transcription factors, tumor suppressors, and activating signaling mutations contribute to the enormous complexity of leukemogenesis.

• #66 Mechanism for Leukemia Cell Growth Discovered Prompting New Treatment Hopes | Technology Networks

  https://www.technologynetworks.com/cancer-research/news/mechanism-for-leukemia-cell-growth-discovered-prompting-new-treatment-hopes-314098

  A mechanism which drives leukemia cell growth has been discovered by researchers at the University of Sussex, who believe their findings could help to inform new strategies when it comes to treating the cancer. […] Leukemia cells are known to have an overactive level of a protein called -catenin, which can drive cancer development. Once this protein moves into the nucleus of cells, where DNA is stored, it can assist the activation of genes important for leukemia development. […] Researchers from the University of Sussex, Bristol and Cardiff using funding from the Kay Kendall Leukaemia Fund (KKLF) and Bloodwise have now discovered a protein partner that promotes this process and therefore helps leukemia cells to grow. […] In a paper published in the journal Haematologica, Dr Rhys Morgan, Lecturer in Biomedical Science, observed that protein LEF-1 can actively control the level of -catenin in the nucleus of myeloid leukemia cells.

• #67 Mechanism for Leukemia Cell Growth Discovered Prompting New Treatment Hopes | Technology Networks

  https://www.technologynetworks.com/cancer-research/news/mechanism-for-leukemia-cell-growth-discovered-prompting-new-treatment-hopes-314098

  From our research findings we’d suggest that pharmacological targeting of -catenin’s movement into the nucleus, through a partner like LEF-1, could be a viable treatment strategy in leukemia. […] However data suggests that anywhere between 20-80% of AML cases display elevated levels of this molecule which justifies further investigation in this setting. […] Dr Morgan and his team are now working to further understand the biological significance of many of the new interacting proteins discovered in the study, with the belief that others could be worth targeting to inhibit -catenin level and activity in leukemia.

• #68 Pathogenesis and Treatment of Leukemia by Harinder Gill, Hardcover | Barnes & Noble®

  https://www.barnesandnoble.com/w/pathogenesis-and-treatment-of-leukemia-harinder-gill/1143490831

  Ch 19 Genomic Landscape of Acute Lymphoblastic Leukaemia (ALL) – Insights to Leukaemogenesis, Prognostications and Treatment. […] Ch 27 Inherited/genetic predisposition to MDS and AML. […] Ch 28 Clonal hematopoiesis and its functional implications in MDS/AML. […] Ch 29 Therapy-related MDS/AML and the role of environmental factors.

• #69 Pathogenesis of TP53-mutated Acute Myeloid leukemia | Laboratory of Daniel C. Link, M.D. | Washington University in St. Louis

  https://linklab.wustl.edu/pathogenesis-of-tp53/

  The long-term goal of this project is to identify genetic and epigenetic alterations that contribute to the development of treatment-related acute myeloid leukemia (tAML) and to exploit this knowledge to develop new therapies for this high-risk subset of AML. […] Mutations of TP53 are enriched in tAML compared to de novo AML with a frequency of 30-40% and 5-10%, respectively. […] Mutations of TP53 are associated with a complex karyotype and very poor overall survival, both for de novo and tAML cases. […] Our recent studies show that in a subset of tAML, mutations of TP53 are the initiating mutation. […] We hypothesize that both cell-intrinsic events and cell-extrinsic stressors contribute to the development of clonal hematopoiesis. We further hypothesize that repeated genotoxic or hematopoietic stress is key to clonal evolution from clonal hematopoiesis to AML.

• #70 Pathogenesis of leukemic syndromes | eClinpath

  https://eclinpath.com/hematology/leukemia/transforming-aligorithm/

  Leukemia pathogenesis […] A transforming event in a hematopoietic stem cell causes genetic mutations resulting in clonal (neoplastic) hematopoietic disorders. Depending on the mutation, the cells can: a) mature abnormally and die prematurely, resulting in cytopenias and myelodysplasia or the myelodysplastic syndromes; b) Proliferate, crowding out normal hematopoiesis, resulting in acute leukemia; or c) Fail to die, accumulating to high numbers in blood, resulting in chronic leukemia. These are not always mutually exclusive events and, due to genomic instability, cells in chronic leukemia and myelodysplastic syndromes can mutate further and evolve into an acute leukemia.

• #71 Overview of Acute Non-Lymphocytic Leukemia Pathogenesis and Recen

  https://www.longdom.org/open-access/overview-of-acute-nonlymphocytic-leukemia-pathogenesis-and-recent-advances-98944.html

  AML pathogenesis may be aided by epigenetic alterations reflecting chromatin changes that affect gene expression in addition to DNA mutations. […] Epigenetic changes have the potential to significantly disrupt and perturb a wide range of key functional intracellular pathways. […] Because epigenetic changes are potentially reversible, they appear particularly amenable to therapeutic interventions and provide appealing avenues for targeted treatment development. […] Current treatment is still largely based on the traditional cornerstones of combination chemotherapy and the appropriate use of stem cell transplantation. […] New conditioning regimens and transplant sources, as well as donor options, have become available.

• #72 Scientists discover a new mechanism for therapy resistance in acute leukemias – Children’s Medical Center Research Institute (CRI) | Dallas Texas

  https://cri.utsw.edu/scientists-discover-a-new-mechanism-for-therapy-resistance-in-acute-leukemias/

  New research has uncovered a previously unknown mechanism that explains why patients with acute myeloid leukemia (AML) often become resistant to common cancer treatments. […] These findings will help researchers investigate the molecular underpinnings, which could lead to new strategies for monitoring AML progression and helping prevent or overcome resistance to targeted cancer therapies. […] The mutations and underlying mechanisms responsible for resistance to IDH inhibition remain largely unknown since developing the appropriate cell models containing IDH mutations has been difficult. […] When the team, led by postdoc fellow Junhua Lyu, Ph.D., integrated these results with targeted sequencing of AML patients and structural and functional studies, they uncovered a new class of IDH second-site mutations responsible for acquired resistance.

• #73 Scientists discover a new mechanism for therapy resistance in acute leukemias – Children’s Medical Center Research Institute (CRI) | Dallas Texas

  https://cri.utsw.edu/scientists-discover-a-new-mechanism-for-therapy-resistance-in-acute-leukemias/

  The presence of IDH second-site mutations prevents the formation of a stable enzyme-inhibitor complex, restores R-2-HG production, and drives therapy resistance in IDH-mutant AML cells and patients. […] Our new cell models and the discovery of new IDH second-site mutations with acquired resistance will likely have broad implications for understanding the molecular basis of therapy resistance in human cancers.

• #74 Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia | Leukemia

  https://www.nature.com/articles/s41375-023-01963-4

  Mutations in mRNA splicing genes has been linked to drug resistance development in AML. […] We show by phosphoproteomics and immunohistochemistry that the phosphorylation of SR proteins increases after the development of acquired resistance to cytarabine. […] Our validation in a cohort of 64 patients with AML proves the usefulness of quantifying phospho-SR protein levels as a predictive biomarker of cytarabine response not linked to the presence of specific mutations in the components of the splicing machinery. […] In sum, we demonstrate that altered phosphorylation of SR proteins is related to primary or secondary resistance to cytarabine, and might be useful to predict response.

• #75 Temple Researchers Discover Drug Resistance Mechanism in Leukemia, Identify Novel Treatment Strategy | Temple Health

  https://www.templehealth.org/about/news/temple-researchers-discover-drug-resistance-mechanism-in-leukemia-identify-novel-treatment-strategy

  Leukemia, a cancer of blood-forming tissues, modulates the bone marrow niche to protect and promote the survival of tumor cells. […] This resistance, the researchers discovered, hinges on overexpression of a molecule known as transforming growth factor beta receptor (TGFR) kinase, which is located on the leukemia cell surface. […] Previous research has shown that leukemia cells displaying deficiency of BRCA1 and BRCA2 proteins are sensitive to PARP inhibition while circulating in the blood. […] We discovered that the same leukemia cells are resistant to the inhibitors in the bone marrow microenvironment. […] Examination of factors in the replicated bone marrow microenvironment identified TGF-1 as an important player in resistance. […] TGF-1, a protein generated by stromal cells in the bone marrow niche, activates TGFR kinase.

• #76 Acute Myeloid Leukemia: From Molecular Pathogenesis to Oral Targeted Therapies

  https://www.uspharmacist.com/article/acute-myeloid-leukemia-from-molecular-pathogenesis-to-oral-targeted-therapies

  Improved understanding of the disease pathogenesis has led to new therapeutic approaches. […] The frequent occurrence of mutations or gene alterations has led to the development of novel agents for the treatment of AML. […] FLT3 mutations are not a leukemic initiating event, but rather a late hit that may account for disease progression. […] FLT3-ITD mutation is associated with an aggressive disease course and is a prognostic marker for rapid relapse and short overall survival after chemotherapy. […] The benefit of combining chemotherapy with small-molecule tyrosine kinase inhibitors may not apply to all broad-spectrum FLT3 kinase inhibitors. […] IDH mutations in human malignancies exclusively affect codon arginine 132 (R132) and codon arginine 172 (R172) in IDH1 and IDH2 (more frequent in AML), respectively.

• #77

  https://journals.lww.com/oncology-times/fulltext/2021/08050/mechanism_of_leukemia_pathogenesis___possible.2.aspx

  So, basically, Lu described that ASXL1 gene mutation is not a loss of function, but actually it is a gain of function through stabilization of BAP1, and that BAP1 hyperactivation caused the changes in gene expression that can result in cancer. […] The new discoveries made by the Northwestern Medicine researchers could lead to inhibitors being developed for all myeloid cancers with ASXL1 gene mutation and hyperactivation of BAP1. […] Because once you know the mechanism of a disease, then you can build targeted therapy that is specific.

• #78 Novel First-in-Class Cancer Drug in Clinical Trials at Sylvester – InventUMPage 1arrow–buttonPage 1arrow–buttonPage 1arrow–buttonPage 1arrow–buttonPage 1arrow–button

  https://news.med.miami.edu/novel-first-in-class-cancer-drug-in-clinical-trials-at-sylvester/

  EP31670 inhibits two types of proteins that contribute to aberrant gene expression, qualifying it as a “first-in-class” medication. […] EP31670’s anti-cancer activity stems from its ability to simultaneously inhibit two types of proteins that contribute to aberrant gene expression. No other single cancer therapy targets this combination, making EP31670 a “first-in-class” medication. […] EP31670’s targets, a group of proteins called BET and the duo CBP/p300, both have epigenetic activity. They regulate the expression of genes. Changes to the packaging of DNA, such as the presence of chemical tags, influence the degree to which the genetic code is available for translation into proteins that drive cancer. […] Researchers have for some time sought to reprogram and deactivate cancer cells by manipulating these and other epigenetic regulators of cancer.

• #79 Novel First-in-Class Cancer Drug in Clinical Trials at Sylvester – InventUMPage 1arrow–buttonPage 1arrow–buttonPage 1arrow–buttonPage 1arrow–buttonPage 1arrow–button

  https://news.med.miami.edu/novel-first-in-class-cancer-drug-in-clinical-trials-at-sylvester/

  Not long afterward, experiments in cells in Sylvester’s labs demonstrated its detrimental effects on leukemia and other cancers. […] Myelofibrosis causes scarring of the bone marrow that interferes with the production of blood cells and causes debilitating symptoms, such as fever and bone pain. In time, myelofibrosis can turn into acute or fast-progressing leukemia. […] EP31670’s targets — the BET proteins called BRD4 and CBP/p300 — control the expression of genes that can cause the progression of myelofibrosis, according to Dr. Watts. Other experimental BET inhibitors that inhibit only BRD4 have shown promise in treating myelofibrosis, a good sign for EP31670’s prospects as a dual inhibitor of BRD4 and CBP/p300, according to Dr. Watts. […] It’s exciting to offer patients a new drug that has a novel mechanism of action in a disease that has poor outcomes, Dr. Watts said. We’ve got to change something, or we make little progress.

• #80 Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia | Leukemia

  https://www.nature.com/articles/s41375-023-01963-4

  Because functional changes in splicing regulatory proteins can promote oncogenesis through overexpression, alteration-of-function, and mutations, therapeutic targeting of the spliceosome holds promise as a novel cancer therapy. […] We show that phosphorylation patterns of SR proteins are altered during the development of cytarabine resistance in AML, and that the combination of spliceosome inhibitors and other approved drugs, including the BCL2 inhibitor venetoclax, improves the therapeutic response in cells from patients with AML, even in a background of cytarabine resistance. […] We demonstrate that posttranslational modifications of splicing factors are involved in cytarabine resistance and can be effectively and safely targeted in AML. […] We confirm the overexpression of SRRM2 in a series of patients with myeloid disease, with a particularly significant increase in expression in AML.

• #81 Priothera Appoints Dr. Jens Hasskarl as Chief Medical Officer to Drive Late-Stage Clinical Development of Mocravimod, a S1P Receptor Modulator for Acute Myeloid Leukemia (AML) | Morningstar

  https://www.morningstar.com/news/globe-newswire/1001094704/priothera-appoints-dr-jens-hasskarl-as-chief-medical-officer-to-drive-late-stage-clinical-development-of-mocravimod-a-s1p-receptor-modulator-for-acute-myeloid-leukemia-aml

  Mocravimod (KRP203) is a synthetic S1P receptor modulator being developed for the adjunctive treatment of AML to enhance the curative potential of allo-HCT. […] Mocravimod’s dual mechanism of action preserves the graft-versus-leukemia (GvL) effect, critical for eliminating cancer cells while reducing the risk of graft-versus-host disease (GvHD), a major complication following allo-HCT. […] Mocravimod is currently the only treatment with the potential to reduce transplant side effects of graft-versus-host disease (GvHD) without compromising the graft’s anticancer effect against leukemia (Graft-versus-Leukemia, or GvL), thereby enhancing the curative potential of allo-HCT.

• #82 Oral Fenbendazole for Cancer Therapy in Humans and Animals | Anticancer Research

  https://ar.iiarjournals.org/content/44/9/3725

  Fenbendazole exhibits several other mechanisms contributing to its anti-cancer effects, primarily by disrupting energy metabolism. […] Studies attribute the anti-cancer mechanisms of fenbendazole to increasing p53 activation, inhibiting the GLUT1 transporter and hexokinase, and reducing glucose uptake in cancer cells. […] Fenbendazole induces mitochondrial translocation of p53, indicating activation of the p53-p21 pathway, which inhibits GLUT transporter expression and prevents glucose uptake in cancer cells. […] Through p53 activation, fenbendazole is believed to impede hexokinase II (HKII), the first glycolytic pathway enzyme critical for cancer cell growth. […] Thus, through targeting GLUT1, HKII, and glycolysis, fenbendazole can lead to cancer cell starvation and reverse drug resistance, aiding cancer treatment.

• #83 Oral Fenbendazole for Cancer Therapy in Humans and Animals | Anticancer Research

  https://ar.iiarjournals.org/content/44/9/3725

  In addition to glycolysis inhibition, fenbendazole induces apoptosis in cancer cells. […] Fenbendazole shows microtubule depolymerizing activity in human cancer cell lines and demonstrates anticancer effects in vitro and in vivo. […] Fenbendazole also causes oxidative stress and activates the MEK3/6-p38MAPK pathway, inhibiting cancer cell proliferation and enhancing apoptosis. […] Fenbendazole’s disruptive effects on energy metabolism are fascinating areas of study that could lead to significant advancements in cancer treatment. […] Various studies in cell lines and animals have demonstrated the efficacy of fenbendazole in inhibiting tumors and targeting drug-resistant cancer cells through glycolysis inhibition.

• #84 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  In a more general sense, it is recognized that residual leukemic stem cells (LSCs) residing in the bone marrow represent a major determinant of treatment failure and lead to early relapse. […] The interaction between programmed cell death-1 (PD-1) and its ligand (PD-L1) functions as an immune checkpoint to promote self-tolerance through suppression of T-cell inflammatory activity. […] The numerous paths that lead to the genesis of leukemia are frequently intertwined, and cooperating mutations involving epigenetic regulators, oncoproteins, transcription factors, tumor suppressors, and activating signaling mutations contribute to the enormous complexity of leukemogenesis.

• #85 Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10693933/

  Acute myeloid leukemia (AML) is a heterogeneous hematopoietic neoplasm which results in clonal proliferation of abnormally differentiated hematopoietic cells. In this review, mechanisms contributing to myeloid leukemogenesis are summarized, highlighting aberrations of epigenetics, transcription factors, signal transduction, cell cycling, and the bone marrow microenvironment. […] The mechanisms contributing to AML are detailed to spotlight recent findings that convey clinical impact. […] Understanding leukemogenesis requires an appreciation of two concepts the function of proteins of commonly mutated genes and how the relevant genes are expressed. […] It is widely recognized that the evolution of AML is unlikely to represent the result of a single biological aberration but instead the consequence of multiple and synergistic aberrations in epigenetic events, cell cycling, proliferation, signal transduction, and apoptosis.

• #86 Acute Myeloid Leukemia: From Molecular Pathogenesis to Oral Targeted Therapies

  https://www.uspharmacist.com/article/acute-myeloid-leukemia-from-molecular-pathogenesis-to-oral-targeted-therapies

  IDH1 or IDH2 mutations tend to be mutually exclusive and confer a neomorphic enzymatic activity, resulting in the reduction of alpha-ketoglutarate to the oncometabolite 2-hydroxyglutarate and leading to epigenetic alterations and impaired hematopoietic differentiation. […] Ultimately, as researchers gain insight into the genetic and epigenetic changes relevant to the pathogenesis of AML, the identification of novel molecular and genetic markers will contribute to an understanding of leukemias biology, leading to improvements in patient risk assessment and the eventual development of novel therapies targeting these molecular or genetic changes.

• #87 CIMB | Special Issue : Molecular Research and Pathological Mechanism of Leukemia

  https://www.mdpi.com/journal/cimb/special_issues/38LMDA69XS

  Molecular Research and Pathological Mechanism of Leukemia […] The high effectiveness of targeted therapies and immunotherapy is associated with limiting the use of traditional chemotherapy. […] The molecular mechanisms involved in leukemia; […] New therapeutic approaches (target therapies including drug design and development).

• #88 Editorial for the Special Issue “Molecular Mechanism of Leukemia”

  https://www.mdpi.com/1422-0067/24/18/13936

  In addition to genetic and epigenetic factors, other facets also contribute significantly to leukemia development, including alterations in cellular metabolism and dysregulated interactions between hematopoietic cells and non-hematopoietic components, further fueling oncogenesis. […] Comprehending the fundamental molecular basis that governs both normal and malignant hematopoiesis is essential for more rational and effective therapeutic interventions.

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