Materiały źródłowe

• #1 Acute myeloid leukemia: Pathogenesis – UpToDate

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

  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. These cells are capable of dividing and proliferating, but cannot differentiate into mature hematopoietic cells (ie, neutrophils). […] This topic reviews the pathogenesis of AML.

• #2 Acute Myeloid Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507875/

  Acute myeloid leukemia (AML) is a rapidly progressing myeloid neoplasm characterized by the clonal expansion of primitive hematopoietic stem cells, known as blasts, in the bone marrow. This expansion results in ineffective erythropoiesis and megakaryopoiesis, clinically manifesting as relatively rapid bone marrow failure compared to chronic and indolent leukemias. This leads to inadequate production of red blood cells and platelets. […] AML is characterized by the clonal proliferation of undifferentiated myeloid precursors, known as blasts, within the bone marrow compartment. Extensive research, both past and ongoing, investigates the communication pathways of these cells within the bone marrow. However, this proliferation primarily stems from the accumulation of diverse genomic and cytogenetic abnormalities. The clinical manifestations of this process result in ineffective erythropoiesis, megakaryopoiesis, and bone marrow failure.

• #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.

• #3 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. […] In addition to histone alternations, DNA methylation and noncoding RNA species also modify transcriptional activity, and collectively constitute an overarching regulatory process of gene expression known as epigenetic modifications.

• #4

  https://haematologica.org/article/view/10945

  Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. […] The current World Health Organization Classification of myeloid neoplasms and leukemia includes eight AML categories defined by recurrent genetic abnormalities as well as three categories defined by gene mutations. […] Acute myeloid leukemia (AML) is a genetically heterogeneous disease with identifiable somatic mutations in 97.3% of all cases. […] Targeted sequencing has identified several mutations that carry prognostic information, including mutations in FLT3, NPM1, KIT, CEBPA and TP53.

• #5 Acute Myeloid Leukemia (AML) – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/leukemias/acute-myeloid-leukemia-aml

  In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers of immature blood cells and replacement of normal marrow by malignant cells. […] Similar to acute lymphoblastic leukemia, acute myeloid leukemia is caused by a series of acquired genetic aberrations. Malignant transformation usually occurs at the pluripotent stem cell level, although it sometimes involves a committed stem cell with more limited capacity for self-renewal. Abnormal proliferation, clonal expansion, aberrant differentiation, and diminished apoptosis (programmed cell death) lead to replacement of normal blood elements with malignant cells. […] Commonly observed cytogenetic abnormalities in AML include t(15;17), trisomy 8, t(8;21), inv(16) or t(16;16) and 11q23.3 rearrangements.

• #6 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 chromosomal translocations encode abnormal fusion proteins, usually transcription factors whose altered properties may cause the „differentiation arrest”. […] Many cells develop mutations in genes that affect epigenetics, such as DNA methylation. […] When these mutations occur, it is likely in the early stages of AML. […] 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.

• #7 Acute myeloid leukemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acute_myeloid_leukemia_pathophysiology

  Much of the diversity and heterogeneity of acute myeloid leukemia stems from the fact that leukemic transformation can occur at a number of different steps along the differentiation pathway. […] Human acute myeloid leukemia is organized as a hierarchy, and the cancer stem cell hypothesis best models the pathophysiology of acute myeloid leukemia. […] Activation of tyrosine kinase receptors is followed by signal transduction via intracellular signal cascades leading to alteration of transcription within the cell nucleus. […] An important pathway that leads to cellular proliferation is the Ras-MAP Kinase pathway, where Ras is activated by binding of guanosine triphosphate (GTP). […] Consequently, there is an activation of MAP kinases, which phosphorylate important transcriptional regulators of cell cycle.

• #7 Acute myeloid leukemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acute_myeloid_leukemia_pathophysiology

  Normal hematopoiesis involves the production of blood cells, and this normal physiologic process is dysregulated in acute myeloid leukemia. The pathophysiology of acute myeloid leukemia involves multiple mechanisms, including altered signal transduction and autonomous proliferation, differentiation blockade, evasion of apoptosis, and self-renewal. […] The malignant cell in acute myeloid leukemia is the myeloblast. However, in acute myeloid leukemia a single myeloblast accumulates genetic changes, which „freeze” the cell in its immature state and prevent differentiation. […] This type of mutation alone does not cause leukemia. However, when such a differentiation arrest is combined with other mutations, which disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of acute myeloid leukemia.

• #8 The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting | Cell Death Discovery

  https://www.nature.com/articles/s41420-022-01193-0

  Type I genetic mutation involves the tyrosine kinases in the signal transduction pathway, including the signaling molecules FMS-like tyrosine kinase-3 (FLT3), stem cell factor receptor (c-Kit), and break point cluster region-abelson (BCR-ABL). […] Type II mutation involves disrupting transcription factors or transcriptional coactivators, such as acute myeloid leukemia-1 transcription factor/eight-twenty-one corepressor (AML1/ETO), mixed-lineage leukemia/ALL1-fused gene from chromosome 9 protein (MLL/AF9), and promyelocytic leukemia/retinoic acid receptor (PML/RAR) fusion gene. […] Recent studies have shown that AML cell populations at relapse may have evolved from either the dominant clonal or minor subclonal cell populations present at diagnosis, accompanied by the potential acquisition of additional mutations.

• #9 ‘Acute myeloid leukemia: a comprehensive review and 2016 update’ | Blood Cancer Journal

  https://www.nature.com/articles/bcj201650

  According to this model, class I mutations which result in the activation of pro-proliferative pathways must occur in conjunction with class II mutations which impair normal hematopoietic differentiation in order for leukemia to develop. Common class I mutations, such as FLT3 (internal tandem duplications, ITD, and tyrosine kinase domain mutations, TKD), K/NRAS, TP53 and c-KIT are found in ~28, 12, 8 and 4% of cases, respectively. […] Enhanced tyrosine phosphorylation of STAT3 whether due to increased secretion of cytokines, such as IL-6 or mutations in receptor tyrosine kinases (for example, FLT3 duplications or less frequently JAK2) is seen in up to 50% of AML cases and signifies a worse prognosis. […] As suggested by the two-hit model, the pathogenesis and behavior of AML depends heavily on the interactions between different somatic alterations and chromosomal rearrangements. Thus, the c-KIT mutation has been associated with t(8;21) or inv(16), and its presence carries significant implications regarding prognosis. Similarly, NMP1 (a class II mutation) frequently occurs in conjunction with the class I mutation FLT3-ITD, or mutations in the epigenetic genes DNMT3A and IDH-1 or IDH-2.

• #10 Targeted Therapy Development in Acute Myeloid Leukemia

  https://www.mdpi.com/2227-9059/11/2/641

  Acute myeloid leukemia (AML) is a hematologic malignancy that is characterized by excessive growth of immature white blood cells (myeloblasts) in the bone marrow and in circulation, intrinsically affecting the process of hematopoiesis. […] The genomic landscape of AML has revealed a wide range of mutations falling into different functional categories of genes that play pivotal roles in AML pathogenesis. […] The most common mutation of AML is in FLT3, which is attributed to the signaling gene category, along with mutations in KIT, PTPN11, RAS, JAK2, and PPM1D. […] Additionally, the genes of DNA methylation exhibited DNMT3A, TET2, IDH1, and IDH2 mutations. […] The classical anthracycline and cytarabine-based chemotherapy for AML lacks durable efficacy and has poor tolerability in older patients.

• #10 Targeted Therapy Development in Acute Myeloid Leukemia

  https://www.mdpi.com/2227-9059/11/2/641

  This unmet medical need demands the development of novel therapeutics for AML. […] Based on prognostic studies of AML derived from clinical outcomes of molecularly defined subsets and from mechanistic disease studies in laboratory models, promising targets for molecularly targeted therapy have been identified in this disease. […] The FDA-approved drugs for AML, beyond standard chemotherapy, include gemtuzumab ozogamicin, hypomethylating agents, FLT3 inhibitors, IDH inhibitors, venetoclax, CPX-351, and hedgehog pathway inhibitors. […] Isocitrate dehydrogenase (IDH) inhibitors have emerged as a promising therapeutic strategy for the treatment of acute myeloid leukemia. […] The most frequent mutations in AML are those in the gene for FMS-like tyrosine kinase 3 (FLT3), which is found in one-third of patients with de novo AML.

• #11 Prognosis and treatment in acute myeloid leukemia: a comprehensive review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-024-00563-w

  Acute myeloid leukemia (AML) is a heterogeneous disorder that is characterized by clonal expansion of immature „blast cells” in the bone marrow and peripheral circulation, resulting in bone marrow failure and inefficient erythropoiesis. […] The formation of AML is linked to the accumulation of acquired genetic and epigenetic changes, mostly in hematopoietic stem and progenitor cells (HSPCs). These changes abnormally modify the cellular and molecular states of HSPCs, converting them into leukemia stem cells. […] Recent studies have demonstrated that AML blasts are the cause of normal hemopoiesis abnormalities. […] The FLT3 gene mutations have been identified as important contributors to leukemogenesis among the several genetic changes linked to AML pathogenesis. […] These mutations cause constitutive activation of the FLT3 signaling, which results in dysregulated proliferation, impaired differentiation, and enhanced survival of leukemic cells.

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

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

  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. […] Similar to the prognostic significance of NPM1mut and biallelic CEBPAmut, core-binding factor (CBF) AML is also associated with a favorable prognosis. […] 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. […] In AML, there are two common constitutively activating FLT3 mutations: an internal tandem duplication (ITD) and a tyrosine kinase domain (TKD) mutation.

• #13 Mechanisms of Resistence of New Target Drugs in Acute Myeloid Leukemia | IntechOpen

  https://www.intechopen.com/chapters/74391

  Uptoday the understanding of leukemogenesis mechanisms have led to the recent approval of FLT3, BCL2 and IDH inhibitors (FLT3i, BCL2i, IDHi). […] FLT3 tirosin kinase receptor mutations determines the constitutive activation and dimerization status of the receptor itself, indipendently from FLT3 ligand binding, and the downstream activation of leukemic cells prolipheration and pro-survival pathways (RAS-NFKB, JAKSTAT, PI3K, BCL2) as showed in Figure 1. […] Isocitrate dehydrogenases are cytoplasmic (IDH1) and mitochondrial (IDH2) enzymes cathalyse the reduction of a-ketoglutarate (a-KG) to citrate in krebs cycle in a NADPH-dependent way. NADPH is important for the reduction of glutathione, which in the reduced state is a major antioxidant and protects the cell against reactive-oxygen species (ROS) and other free radicals. IDH mutations have a loss of function effect, producing the accumulation of the oncometabolite R2-hydroxyglutarate (2-HG) which competitively inhibits multiple -ketoglutarate dependent dioxygenases such as lysine (K)-specific demethylase (KDM) and ten eleven translocation methylcytosine dioxygenase 2 (TET2), causing widespread epigenetic changes with global dysregulation of gene expression and abnormal differentiation and proliferation of leukemic cells.

• #14 Clinical implications of recurrent gene mutations in acute myeloid leukemia | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-020-00161-7

  Acute myeloid leukemia (AML) is a genetically heterogeneous clonal malignancy characterized by recurrent gene mutations. […] The recurrent gene mutations and their important roles in acute myeloid leukemia (AML) pathogenesis have been studied extensively. […] Certain genes have been proved to be specifically related to the leukemia pathogenesis, such as pre-leukemic cell identification, particularly in AML patients with mutated DNMT3A and TET2. […] The important clinical point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in AML patients. […] Patients with FLT3-ITD have a high risk of relapse and low cure rates. […] Risk associated to FLT3-ITD in patients with AML may depend on mutational burden and its interaction with other mutations.

• #15 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

  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. […] IDH mutations 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.

• #16 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. […] 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. […] 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.

• #17 Genomic landscape in acute myeloid leukemia and its implications in risk classification and targeted therapies | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-020-00674-7

  The discovery of molecular genetic alterations has led to the refinement of prognostication in AML. […] Deregulation of epigenetic modifiers, including alterations in DNA methylation, DNA hydroxymethylation and histone modifications, such as methylation, acetylation, phosphorylation, sumoylation and ubiquitination etc., is now recognized as an important mechanism in the pathogenesis of AML. […] Mutations in IDH, MLL, and EZH2 mutations in which targeted agents are either available in clinical use or under investigation. […] The impact of IDH mutations on prognosis remains to be elucidated. […] The presence of MLL rearrangements usually predict aggressive course and poor outcome. […] The findings offer a potentially attractive therapeutic approach in AML with EZH2 mutations and the EZH2 inhibitor is currently under development or early phase trials.

• #18 Mechanism of Pathway: Considerations of Cytogenetic and Molecular Mutation Status for Patients with Acute Myeloid Leukemia: A Deeper Look at the Role of Diagnostic and Ongoing Testing Across the Care Continuum – Oncology Practice Management

  https://oncpracticemanagement.com/special-issues/considerations-of-cytogenetic-and-molecular-mutation-status-for-patients-with-acute-myeloid-leukemi/1116:tlg1545

  After 30 years with few therapeutic advances, the past decade has witnessed significant developments in our knowledge of the pathogenesis of AML and, subsequently, in the treatment landscape. Although the pathogenesis of AML has not been completely defined, chromosomal rearrangements and molecular changes have been implicated in its development. Comprehensive genomic analyses have shown that multiple molecular pathways drive progression of this clonal hematopoietic disorder. Abnormal karyotypes with recurrent chromosomal structural variations have been identified in approximately 45% to 55% of patients with AML. A study of leukemia genes in 1540 patients in 3 clinical trials of intensive AML treatment identified at least 1 driver mutation in 96% of patients and 2 driver mutations in 86% of patients. Mutations in genes that encode epigenetic modifiers, such as DNMT3A, ASXL1, and TET2, are often acquired early and are present in the founding clone. However, in the general population, these mutations are also found to be acquired as a function of age and do not always result in the development of disease. According to the two-hit hypothesis, additional cooperating mutations are needed to generate the malignant founding clone in AML. […]

• #19 Uncovering the genetic mechanism driving acute myeloid leukemia – Oncology Central

  https://www.oncology-central.com/uncovering-genetic-mechanism-driving-acute-myeloid-leukemia/

  Researchers have begun to uncover the genetic mechanisms by which acute myeloid leukemia cells with a DNMT3A mutation stay as undifferentiated cells, rather than developing into healthy mature hematocytes. […] Through the development of the first laboratory model of acute myeloid leukemia (AML), the team studied somatic mutations in the DNA methyltransferase 3A gene (DNMT3A), which are found in approximately 20-30% of AML cases. Using this mouse model, they demonstrated that mutations in DNMT3A promote acute leukemogenicity in the presence of mutant NRAS, induce DNA hypomethylation of key stemness genes and potentiate stemness gene expression. […] Our findings not only provide a deeper understanding of how this prevalent mutation contributes to the development of AML, but it also offers useful information on how to develop new strategies to treat AML patients.

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

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

  DNA methylation is the most well-studied epigenetic modification in AML. […] In neoplastic development, the degree of CpG-island hypermethylation (as observed in leukemia and lymphoma) or global genomic hypomethylation (as observed in colon, lung, or breast cancer) increases with progression from a benign to a malignant state. […] In the absence of these agents, re-methylation is commonly observed and is thought to culminate in disease relapse. […] 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. […] Cytosolic isocitrate dehydrogenase (IDH1) and its mitochondrial homolog (IDH2) are enzymes involved in the citric acid cycle that convert isocitrate to -ketoglutarate.

• #21 Acute Myeloid Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507875/

  Genetic abnormalities that characterize favorable risk disease include chromosomal translocations t(8;21)(q22;q22.1) or inv(16)(p13.1q22). […] Runt-related transcription factor (RUNX1) is an essential component of hematopoiesis and is also known as AML1 protein or core-binding factor subunit alpha-2 (CBFA2). RUNX1 is located on chromosome 21 and is frequently translocated with the ETO (Eight Two One)/RUNX1T1 gene located on chromosome 8q22, creating an AML-ETO or t(8;21)(q22;q22) AML, which is seen in about 12% of AML cases. […] Mutations in isocitrate dehydrogenase (IDH) are oncogenic and present in 15% to 20% of all AML cases and 25% to 30% of patients with cytogenetically normal AML, with a higher prevalence in older individuals. Additionally, TP53 mutations are associated with a poor prognosis and resistance to chemotherapy.

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

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

  The leukemogenic mechanism of IDH1/2mut is due to the production of an aberrant metabolite, 2-hydroxyglutarate (2HG), a structural analog of -ketoglutarate. […] The bromodomain (BRD)-containing proteins are epigenetic modifiers that bind to acetylated lysine on histones. […] Maintenance of AML was found to operate through BRD4-mediated MYC activation, creating persistent self-renewal, while inhibition of BRD4 resulted in cell cycle arrest and induction of apoptosis. […] Unlike the BRD-containing proteins, which function primarily as the readers of histone acetylation, histone acetyltransferases are responsible for the addition of acetyl groups to lysine residues. […] EZH2 is a histone methyltransferase that trimethylates lysine 27 of histone 3 (H3K27me3), creating a repressive transcriptional signature.

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

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

  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. […] The native function of MLL is to maintain the activity of target genes through what was historically thought to be the histone 3 lysine 4 (H3K4) methyltransferase activity of the MLL protein. […] 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 CCAAT-enhancer binding protein alpha (CEBP) is a transcription factor that regulates differentiation and proliferation in myeloid progenitors. […] Nucleophosmin (NPM1) is a multifunctional nucleocytoplasmic shuttling phosphoprotein that is found primarily in the nucleolus.

• #24 Prognosis and treatment in acute myeloid leukemia: a comprehensive review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-024-00563-w

  FLT3 mutations cause the equilibrium of hematopoietic cell populations to be disrupted, which promotes the growth of undifferentiated blasts and inhibits the development of normal hematopoietic cells. […] NPM1 mutations are associated with a favorable outcome and frequently coexist with FLT3 mutations, especially the ITD-type variants. […] The majority of NPM1 mutations are 4-bp insertions that frameshift in the last few C-terminal amino acids, resulting in the deletion of W288 and W290 (or W290 alone) and the generation of a new C-terminal NES. […] The cytoplasmic location of NPM1 mutants requires both modifications. […] The PTPN11 mutation is inversely associated with FLT3/ITD but strongly linked with older age, normal karyotype, FAB M4/M5 subtypes, CD14 expression, and the NPM1 mutation.

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

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

  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. […] Similar to the prognostic significance of NPM1mut and biallelic CEBPAmut, core-binding factor (CBF) AML is also associated with a favorable prognosis. […] 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. […] In AML, there are two common constitutively activating FLT3 mutations: an internal tandem duplication (ITD) and a tyrosine kinase domain (TKD) mutation.

• #26 Insights into the New Molecular Updates in Acute Myeloid Leukemia Pathogenesis

  https://www.mdpi.com/2073-4425/14/7/1424

  The ICC has recognized RUNX1 mutations as myelodysplasia-related in AML, and therefore, cases of myeloid neoplasms with ≥10–19% blasts in the bone marrow are defined as MDS/AML, while cases with ≥20% blasts are defined as AML with myelodysplasia-related gene mutations (RUNX1). […] The WHO5 would classify cases with ≥20% blasts as AML and provide subtyping based on differentiation in the absence of other specific genetic alterations. […] The CCAAT/enhancer binding protein α (C/EBP-α) transcription factor is encoded by the CEBPA gene on the long arm of chromosome 19. […] Numerous studies of CEBPA mutations in AML found an improved prognosis in patients with biallelic mutations, with each allele harboring a mutation from each of these clusters. […] This finding led to the WHO4R entity of “AML with biallelic mutation of CEBPA.”

• #27 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. […] To date, only 22 tAML genomes have been sequenced. Clearly, additional cases must be characterized to understand the full spectrum of sensitizing mutations (like TP53), patterns of cooperating mutations, structural variants, and epigenomic events that contribute to the progression of tAML.

• #28 The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting | Cell Death Discovery

  https://www.nature.com/articles/s41420-022-01193-0

  Acute myeloid leukemia (AML) is a hematological malignancy characterized by cytogenetic and genomic alterations. […] Recently, it has been pointed out that leukemic stem cells (LSCs) are the fundamental cause of drug resistance and AML relapse. […] LSCs represent a subpopulation of malignant cells with unlimited self-renewal capacity and multi-directional differentiation potential. […] This feature of the BMM can lead to the generation of dominant clones, resulting in leukemia relapse and drug resistance. […] Therefore, an in-depth investigation of the relationship between LSCs and the BMM, as well as the generation and evolution laws of LSCs, will facilitate the understanding of the pathogenesis and drug resistance mechanism of AML. […] The BM is the principal hematopoietic organ consisting of HSCs and the hematopoietic microenvironment.

• #29 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. Stromal elements are important in the homing of immature HC or hematopoietic stem cells. 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.

• #30 The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting | Cell Death Discovery

  https://www.nature.com/articles/s41420-022-01193-0

  The BMM exerts a selective pressure for the clonal evolution in leukemia. […] Elevated reactive oxygen species (ROS) levels are hallmark features of leukemia cells, and oxidative stress induced by high level of ROS may represent another selective pressure for the clonal evolution in leukemia. […] The interactions between LSCs and the microenvironment are fundamental to survival, therapeutic resistance, and relapse of leukemia. […] BMM is not only the place where LSCs are generated, but also serves as a sanctuary for these malignant cells and provides support for their clonal evolution, reinforcing its involvement in the occurrence of drug resistance and recurrence of leukemia.

• #31 The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting | Cell Death Discovery

  https://www.nature.com/articles/s41420-022-01193-0

  The dysfunction of BMSCs will trigger and promote the development of malignant hematological diseases. […] Many studies have reported that AML is linked with a reduction in BMSCs. […] The occurrence of donor cell leukemia in clinical AML cases further indicates that the hematopoietic microenvironment may be involved in the pathology of AML. […] Recent evidence suggested that oxidative stress may play a key role: […] In contrast, the implantation of PTEN-deficient whole bone marrow cells led to myeloproliferative progression to leukemia/lymphoma. […] These results suggested that BMSCs may play a more critical role in the malignant transformation of normal hematopoietic cells into leukemia cells. […] It is generally believed that LSC result from mutation accumulation in HSC. […] According to the AML two-hit model, two major types of genetic mutations play a pivotal role in the pathogenesis of AML.

• #32 Molecular pathogenesis of Acute Myeloid Leukemia – ICVS

  https://icvs.uminho.pt/project/molecular-pathogenesis-of-acute-myeloid-leukemia/

  During AML development, a remarkable microenvironment remodeling of the bone marrow (BM) is observed, suggesting that clonal HSCs may communicate differently with BM stromal cells such as mesenchymal stem cells (MSCs). […] Intercellular communication is a complex process mediated by a variety of chemical and mechanical signals, and for which extracellular vesicles (EVs) play an important role.

• #33

  https://link.springer.com/article/10.1007/s12185-024-03837-6

  Acute myeloid leukemia (AML) develops when hematopoietic stem cells acquire chromosomal and genetic abnormalities, transforming into leukemia stem cells (LSCs) and further gaining driver mutations. Advances in genomic analysis have identified numerous new gene mutations involved in AML development. Recent research has shown that individuals with germline mutations in genes like DDX41 and CEBPA develop AML upon acquiring additional somatic mutations, and the latest WHO classification separates AML with such mutations into distinct disease groups. LSCs are regulated by different metabolic processes than normal stem cells, contributing to drug resistance and relapse. LSCs rely on oxidative phosphorylation (OXPHOS) metabolism for energy production, and venetoclax inhibits this process, affecting LSCs. Resistant LSCs show enhanced glycolysis, which suggests that targeting both OXPHOS and glycolysis is crucial. While targeted therapies like FLT3, BCL-2, and IDH inhibitors have shown efficacy, resistance remains an issue, highlighting the need for new treatment strategies.

• #34

  https://link.springer.com/article/10.1007/s12185-024-03837-6

  Acute myeloid leukemia (AML) arises when hematopoietic stem cells acquire several chromosomal and genetic abnormalities, transforming into leukemia stem cells (LSCs). These LSCs further accumulate driver gene mutations, leading to the development of AML. These acquired molecular abnormalities lead to variation in the morphological and pathological characteristics of leukemic cells, as well as the clinical outcomes of treatments such as chemotherapy and hematopoietic stem cell transplantation. Thus, AML is a heterogeneous group of diseases, making genomic analysis indispensable for its diagnosis. […] Advancements in genomic analysis using next-generation sequencers have led to the discovery of many novel gene mutations involved in various AML pathologies. As hematopoietic stem cells age, they can accumulate a certain number of acquired genetic mutations without functional issues. However, the increased acquisition of mutations with aging significantly raises the likelihood of developing myeloid hematopoietic tumors. Additionally, individuals with germline-derived genetic mutations can develop AML through acquisition of additional somatic mutations, which are defined as subtypes of myeloid neoplasms associated with germline predisposition in the latest WHO classification of AML. Genes such as CEBPA, RUNX1, TP53, and GATA2 have different pathological mechanisms in AML with germline mutations than in AML with acquired mutations. New mechanisms of myeloid tumor development involving genes like DDX41, ETV6, and ANKRD26 are garnering attention for their potential in elucidating disease pathology and serving as novel therapeutic targets.

• #35

  https://link.springer.com/article/10.1007/s12185-024-03837-6

  In addition to progress in understanding genetic mutations and pathologies of AML through genomic analysis, it has recently become clear that LSCs maintain their stemness through metabolic pathways distinct from normal hematopoietic stem cells, playing a crucial role in drug resistance and relapse in AML. Notably, AML LSCs are metabolically dormant and heavily rely on oxidative phosphorylation (OXPHOS) metabolism rather than glycolysis for energy production. Venetoclax which is bcl-2 inhibitor is thought to work not only by inhibiting the anti-apoptotic protein BCL2 but also by effectively impairing dormant LSCs through OXPHOS inhibition. However, LSCs resistant to venetoclax and other chemotherapeutic agents such as anthracyclines and cytarabine have been found to exhibit increased NAD+ levels, hexokinase 1 activity, and lactate production, indicating enhanced glycolysis compared to de novo AML LSCs. This suggests the importance of targeting glycolysis in addition to OXPHOS metabolism in treatment of resistant AML LSCs.

• #36 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. […] 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).

• #37 The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting | Cell Death Discovery

  https://www.nature.com/articles/s41420-022-01193-0

  Type I genetic mutation involves the tyrosine kinases in the signal transduction pathway, including the signaling molecules FMS-like tyrosine kinase-3 (FLT3), stem cell factor receptor (c-Kit), and break point cluster region-abelson (BCR-ABL). […] Type II mutation involves disrupting transcription factors or transcriptional coactivators, such as acute myeloid leukemia-1 transcription factor/eight-twenty-one corepressor (AML1/ETO), mixed-lineage leukemia/ALL1-fused gene from chromosome 9 protein (MLL/AF9), and promyelocytic leukemia/retinoic acid receptor (PML/RAR) fusion gene. […] Recent studies have shown that AML cell populations at relapse may have evolved from either the dominant clonal or minor subclonal cell populations present at diagnosis, accompanied by the potential acquisition of additional mutations.

• #38 Acute myeloid leukemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acute_myeloid_leukemia_pathophysiology

  Much of the diversity and heterogeneity of acute myeloid leukemia stems from the fact that leukemic transformation can occur at a number of different steps along the differentiation pathway. […] Human acute myeloid leukemia is organized as a hierarchy, and the cancer stem cell hypothesis best models the pathophysiology of acute myeloid leukemia. […] Activation of tyrosine kinase receptors is followed by signal transduction via intracellular signal cascades leading to alteration of transcription within the cell nucleus. […] An important pathway that leads to cellular proliferation is the Ras-MAP Kinase pathway, where Ras is activated by binding of guanosine triphosphate (GTP). […] Consequently, there is an activation of MAP kinases, which phosphorylate important transcriptional regulators of cell cycle.

• #39 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).

• #40 Acute myeloid leukemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acute_myeloid_leukemia_pathophysiology

  As a consequence of these, there is autonomous increased proliferation of cells. […] Altered gene expression leads to autonomous cellular proliferation with defects in regulatory pathways involved in cellular proliferation. […] Chromosomal translocations and point mutations both play a pivotal role in generating a differentiation blockade on myeloid cells. […] The increased expression of Bcl-2 pro-survival molecule plays a key role in evasion of programmed cell death in AML. […] The myeloid cells in acute myeolid leukemia have an ability to self-renew without being committed to a specific cell lineage. […] The self-renewing capacity of myeloid cells in AMLs is thought to be mediated by the following: Fusion of ALK tyrosine kinase with nucleophosmin protein (NPM).

• #41 Hematologic Malignancies:Acute Myeloid Leukemia (AML)

  https://www.abbviepro.com/gu/en/Home/Oncology/Tumor-Types/Hematologic-Malignancies-Acute-Myeloid-Leukemia-AML.html

  Both de novo and secondary AML develop through a multistep process that involves the acquisition of a variety of genetic alterations, which may induce: A block in cell differentiation, Increased cell proliferation, An adverse impact on epigenetic control. […] More specifically, genetic alterations and abnormalities contribute to AML pathogenesis due to their effects on tumor suppressor genes and the dysregulation of intracellular signaling pathways, apoptosis, epigenetic mechanisms, and mitochondrial metabolism. […] An increased understanding of the pathophysiology of AML has facilitated the development of novel, molecularly targeted therapies. However, these recent additions may only benefit certain patients due to the heterogeneity of the disease. […] The BCL-2 protein is overexpressed in up to 70% of AML cases; elevated levels of BCL-2 correlate with poor prognosis and chemoresistance.

• #42 Acute Myeloid Leukemia (AML): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/197802-overview

  The changes in the bone marrow result in two disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. […] Second, the rapid proliferation of the abnormal myeloblasts, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, the blood, and, frequently, the spleen and liver.

• #43 Adult myeloid leukaemias: pathogenesis, clinical features and classification – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/adult-myeloid-leukaemias-pathogenesis-clinical-features-and-classification

  During recent years, significant progress has been made in understanding the development of these diseases at a molecular level; this has led to important advances in risk stratification and treatment strategies. […] For most cases of AML, CML and MDS the cause is unknown, but certain risk factors (eg, exposure to ionising radiation) have been identified. Furthermore, previous exposure to chemotherapy (particularly alkylating agents and topoisomerase-II inhibitors) can predispose individuals to secondary MDS and AML. A link has also been demonstrated between exposure to benzene, pesticides, herbicides and some dyes and the development of AML. Certain genetic disorders (eg, Down’s syndrome, Fanconi anaemia) are also associated with an increased risk of AML. […] In the case of AML, the most common mutation occurs in the FLT3 tyrosine kinase receptor gene. This mutation is associated with a poor prognosis and is being targeted specifically by a number of novel therapies for AML.

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

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

  Previous cancer treatment. Past cancer treatments involving radiation or chemotherapy may increase the likelihood youll develop some types of leukemia. […] Smoking. If you have a history of smoking or exposure to second-hand smoke, youre at increased risk of developing acute myelogenous leukemia. […] Exposure to industrial chemicals. Benzene and formaldehyde are known cancer-causing chemicals found in building materials and household chemicals. […] Genetic disorders, such as neurofibromatosis, Klinefelter syndrome, Schwachman-Diamond syndrome and Down syndrome, may increase your risk. […] Research suggests that some types of leukemia may run in families. In most cases, however, having a relative with leukemia doesnt mean that you or another family member will also develop leukemia.

• #45 Acute Myeloid Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507875/

  The European LeukemiaNet (ELN) 2022 consensus recommendations offer a valuable framework for classifying AML based on mutational profile. However, before providers can truly grasp and access this framework, they need to comprehend the origins and pathways of the disease. […] Patients with myeloproliferative neoplasms, which include myelofibrosis, essential thrombocythemia, polycythemia vera, and chronic myeloid leukemia, may also progress or evolve into a higher-grade myeloid neoplasm such as AML. […] Another group of patients at risk for AML includes patients who have previously received chemotherapy for other malignancies. […] Additional environmental exposures, including radiation, tobacco smoke, and benzene, also contribute to the risk of AML. […] AML is a highly heterogeneous disease that requires individualized cytogenetic and molecular characterization. However, broadly speaking, the disease can be categorized into favorable, intermediate, or high-risk groups based on the criteria outlined in the aforementioned ELN 2022 guidelines.

• #46 Acute myeloid leukemia | eClinpath

  https://eclinpath.com/hematology/leukemia/leukemia-types/acute-myeloid-leukemia/

  And we should also not forget the microenvironment, which also provides protective niches for leukemic stem cells and may modulate and even trigger leukemogenesis in AML. […] Data in murine models indicates that leukemic cells cause a state of irreversible senescence in mesenchymal stromal cells in marrow, with subsequent release of cytokines and other factors that promote persistence and proliferation of the tumor cells.

• #47 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

  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. […] 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.

• #48

  https://haematologica.org/article/view/10945

  Consistently, the recurrent genetic abnormalities defining subtypes of AML are associated with distinctive clinicopathological features, impact prognosis, and are influencing treatment choices. […] Although new molecular analysis techniques such as ultra-deep sequencing have helped to identify numerous recurrent genetic abnormalities, to date, only a limited number have been incorporated into risk-stratification schemes such as the National Comprehensive Cancer Network or European LeukemiaNet (ELN) guidelines. […] Since 2017, eight new targeted drugs have been approved by the Food Drug Administration (FDA) and six by the European Medicines Agency (EMA). […] Targeting FLT3-kinase signaling is particularly important given that approximately one third of AML patients have a FLT3 mutation.

• #49 Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic

  https://dx.doi.org/10.1101/gad.349368.122

  Despite FDA approval of nine new drugs for patients with acute myeloid leukemia (AML) in the United States over the last 4 years, AML remains a major area of unmet medical need among hematologic malignancies. […] In this review, we discuss the development of promising new molecular targeted approaches for AML, including menin inhibition, novel IDH1/2 inhibitors, and preclinical means to target TET2, ASXL1, and RNA splicing factor mutations. […] In addition, we review progress in immune targeting of AML through anti-CD47, anti-SIRP, and anti-TIM-3 antibodies; bispecific and trispecific antibodies; and new cellular therapies in development for AML.

• #50 Mechanism of Pathway: Considerations of Cytogenetic and Molecular Mutation Status for Patients with Acute Myeloid Leukemia: A Deeper Look at the Role of Diagnostic and Ongoing Testing Across the Care Continuum – Oncology Practice Management

  https://oncpracticemanagement.com/special-issues/considerations-of-cytogenetic-and-molecular-mutation-status-for-patients-with-acute-myeloid-leukemi/1116:tlg1545

  Many factors, including age, fitness, cytogenetics, and molecular analysis, are taken into consideration when developing a treatment strategy for patients with AML. The combination of cytogenetic information provided by karyotype analysis and the identification of molecular abnormalities is crucial to the management of patients with the disease, as it provides invaluable prognostic information regarding remission rates, relapse risk, and overall survival (OS) outcomes. […] […] As discussed, AML is a heterogeneous disease characterized by a high degree of recurrent genetic alterations. In addition to their importance when subclassifying AML, cytogenetic analysis and mutation status are useful for predicting prognosis, and may help guide treatment strategies. It is important to note that the prognostic impact of many markers is context-dependent. Gene-gene interactions occur, with the effect of a given abnormality dependent on the presence and/or absence of another. […]

• #51 Mechanism of Pathway: Considerations of Cytogenetic and Molecular Mutation Status for Patients with Acute Myeloid Leukemia: A Deeper Look at the Role of Diagnostic and Ongoing Testing Across the Care Continuum – Oncology Practice Management

  https://oncpracticemanagement.com/special-issues/considerations-of-cytogenetic-and-molecular-mutation-status-for-patients-with-acute-myeloid-leukemi/1116:tlg1545

  Some mutations, including FLT3-ITD, are associated with poor prognosis. Mutation status should be a key consideration in treatment strategies; thus, timely molecular testing is crucial at diagnosis. In addition, the mutations present at relapse may differ from those present at initial diagnosis. Therefore, it may be important to perform genetic testing not only at diagnosis, but at multiple times across the care continuum for patients with AML.

• #52 Rewriting the Rules of AML Therapy: How SENTI-202 Strikes a Critical Balance in CAR-NK Cell Treatment – GeneOnline News

  https://www.geneonline.com/rewriting-the-rules-of-aml-therapy-how-senti-202-strikes-a-critical-balance-in-car-nk-cell-treatment/

  The accelerator CAR initiates cancer cell killing when CD33 or FLT3 are detected, driving the immune cells to target malignant cells. The combination of these two markers helps improve the recognition of leukemia blasts and leukemic stem cells (LSCs), which are often responsible for relapse and disease progression. […] The brake mechanism, in the form of an inhibitory receptor targeting endomucin (EMCN), ensures that healthy cells remain unharmed even if the healthy cells express CD33 and/or FLT3, since EMCN is generally found higher on healthy cells compared to AML cells. […] Despite promising technologies, treating AML remains extremely challenging. Its a difficult disease to address, Dr. Rajangam admitted. Not only because leukemia itself can be resistant to therapy, but also because this is a disease of the elderly, so a lot of patients have other illnesses like cardiac problems or infections, which makes it difficult to give them the drugs they need. […] Both CD33 and FLT3 are important drivers of AML, Dr. Lu pointed out. We know that inhibiting CD33 works for AML. We know that turning off the FLT3 pathway works for AML. So from that perspective, these targets are well-understood in the field.

• #53 Rewriting the Rules of AML Therapy: How SENTI-202 Strikes a Critical Balance in CAR-NK Cell Treatment – GeneOnline News

  https://www.geneonline.com/rewriting-the-rules-of-aml-therapy-how-senti-202-strikes-a-critical-balance-in-car-nk-cell-treatment/

  At the 2025 AACR Annual Meeting, Senti Biosciences shared new clinical data from its first-in-human study of SENTI-202, a next-generation allogeneic CAR-NK cell therapy designed to tackle one of the most complex hematologic cancersacute myeloid leukemia (AML). Despite decades of research, AML remains difficult to treat due to its heterogeneity, rapid progression, and resistance to standard therapies. […] Senti Bios SENTI-202 is built with a novel multi-target logic gate that aims to improve the specificity and efficacy of AML treatments. AML is a complex cancer marked by the uncontrolled growth of immature white blood cells in the bone marrow. Traditionally, AML therapies have faced challenges in selectively targeting cancer cells without also harming healthy tissues. […] One difficulty in treating AML lies in its heterogeneity. Its not a single disease but a collection of subtypes, making it hard to treat with only one individual target. In addition, known AML targets are also expressed on healthy cells, resulting in significant toxicity against healthy cells during treatment.

• #54 Mechanisms of Resistence of New Target Drugs in Acute Myeloid Leukemia | IntechOpen

  https://www.intechopen.com/chapters/74391

  New drugs targeting single mutations have been recently approved for Acute Myeloid Leukemia (AML) treatment, but allogeneic transplant still remains the only curative option in intermediate and unfavorable risk settings, because of the high incidence of relapse. […] Primary and secondary AML resistance to new target agents is actually an intriguing issue and some of these mechanisms have already been explored and identified. Changes in mutations, release of microenvironment factors competing for the same therapeutic target or promoting the survival of blasts or of the leukemic stem cell, the upregulation of the target-downstream pathways and of proteins inhibiting the apoptosis, the inhibition of the cytochrome drug metabolism by other concomitant treatments are some of the recognized patterns of tumor escape.

• #55 Mechanisms of Resistence of New Target Drugs in Acute Myeloid Leukemia | IntechOpen

  https://www.intechopen.com/chapters/74391

  The knowledge of these topics might implement the model of the AML umbrella trial study through the combinations or sequences of new target drugs, preemptively targeting known mechanisms of resistance, with the aim to improve the potential curative rates, expecially in elderly patients not eligible to transplant.

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