Materiały źródłowe

• #1 Chronic Myelogenous Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK531459/

  Chronic myelogenous leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative neoplasm predominantly composed of proliferating granulocytes and determined to have the Philadelphia chromosome/translocation t(9;22)(q34;q11.2). CML affects both the peripheral blood and the bone marrow. […] The fusion oncoprotein BCR-ABL1 defines CML. 90% to 95% of patients with CML have a shortened chromosome 22 because of a reciprocal translocation t(9;22) (q34;q11.2) called the Philadelphia chromosome. The ABL1 gene encodes a non-receptor tyrosine kinase on chromosome 9, and BCR is a breakpoint cluster region on chromosome 22. The translated oncoprotein, in most cases, is 210-kd and called p210 BCR-ABL1. Alternative splicing results in p190 and p230 BCR-ABL1, which may show different presentations. This oncoprotein acts as a constitutively expressed defective tyrosine kinase. The downstream pathways affected include JAK/STAT, PI3K/AKT, and RAS/MEK; they involve cell growth, cell survival, inhibition of apoptosis, and activation of transcription factors. […] The remainder of patients have variant or complex translocations involving additional chromosomes detected by routine cytogenetics or a cryptic BCR-ABL1 translocation detected with fluorescent in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (PCR).

• #2 Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10084831/

  Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase, the acceleration phase, and the blast phase. Pathophysiology of CML revolves around Philadelphia chromosome that constitutively activate tyrosine kinase through BCR-ABL1 oncoprotein. […] The presence of BCR-ABL1 fusion gene in hematopoietic stem cells has been shown to be sufficient for initiation of CML. Thus, the pathophysiology of CML revolves around the BCR-ABL1 fusion gene. Approximately 90% to 95% of patients with CML have reciprocal translocation of t(9;22) (q34;q11.2). This results in a shortened chromosome 22, termed Philadelphia chromosome, containing the BCR-ABL1 oncogene. […] As has been described by much of the scientific literature on this topic, the BCR-ABL1 hybrid gene located on the Ph chromosome synthesizes the oncoprotein 210 kD (p210), which plays a role in leukemogenesis of CML. The p210BCR-ABL1 protein can continuously activate the tyrosine kinase pathway, resulting in an increase in the signal transduction of unregulated downstream oncogenic pathways such as JAK/STAT, PI3K/AKT, RAF, MYC, and RAS/MEK. All of these pathways are involved in cell growth, cell survival, and the inhibition of apoptosis. Thus, HSCs with BCR-ABL1 translocation have a proliferative advantage due to their enhanced response to growth factors.

• #3 Chronic Myeloid Leukemia (CML) – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/leukemias/chronic-myeloid-leukemia-cml

  Chronic myeloid leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of mature and immature granulocytes. […] The Philadelphia (Ph) chromosome is present in 90 to 95% of cases of chronic myeloid leukemia. The Ph chromosome is the product of a reciprocal translocation between chromosomes 9 and chromosome 22, t(9;22). During this translocation, a piece of chromosome 9 containing the oncogene ABL is translocated to chromosome 22 and fused to the BCR gene. The chimeric fusion gene BCR-ABL is responsible for production of the oncoprotein bcr-abl tyrosine kinase. […] The bcr-abl oncoprotein has uncontrolled tyrosine kinase activity, which deregulates cellular proliferation, decreases adherence of leukemia cells to the bone marrow stroma, and protects leukemic cells from normal programmed cell death (apoptosis).

• #4 Azthena logo with the word Azthena

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

  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. […] 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.

• #5 Azthena logo with the word Azthena

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

  A portion of chromosome 9 moves to the end of chromosome 22 and a portion of chromosome 22 moves to the end of chromosome 9. This process is called translocation. The translocation of chromosome 9 and chromosome 22 is found only in CML cells. […] This gene is called BCR-ABL cancer causing gene. […] The break on chromosome 22 involves a gene called BCR that stands for breakpoint cluster region. The ABL gene moves to chromosome 22 and fuses with the remaining portion of the BCR gene. This results in a leukemia-causing fusion gene BCR-ABL gene. […] 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.

• #6 Chronic myelogenous leukemia – Wikipedia

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

  In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR („breakpoint cluster region”) gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal „fusion” gene generates a protein of p210 or sometimes p185 weight (p210 is short for 210 kDa protein, a shorthand used for characterizing proteins based solely on size). Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the bcr-abl fusion gene product is also a tyrosine kinase. […] The fused BCR-ABL protein interacts with the interleukin 3beta(c) receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins that control the cell cycle, speeding up cell division. Moreover, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia. With improved understanding of the nature of the BCR-ABL protein and its action as a tyrosine kinase, targeted therapies (the first of which was imatinib) that specifically inhibit the activity of the BCR-ABL protein have been developed. These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of bcr-abl as the cause of CML.

• #7 Chronic Myelogenous Leukemia (CML): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/199425-overview

  This translocation relocates an oncogene called ABL from the long arm of chromosome 9 to a specific breakpoint cluster region (BCR) in the long arm of chromosome 22. The ABL oncogene encodes a tyrosine protein kinase. The resulting BCR::ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype, through processes that are not yet fully understood. […] The presence of BCR::ABL rearrangement is the hallmark of CML, although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML. […] The initiating factor of CML is still unknown, but exposure to ionizing radiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki. Other agents, such as benzene, are possible causes.

• #8 What Causes Chronic Myeloid Leukemia? | American Cancer Society

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

  Over the past few years, scientists have made great progress in understanding how certain changes in DNA can cause normal bone marrow cells to become leukemia cells. In no cancer is this better understood than in chronic myeloid leukemia (CML). […] Most cases of CML start during cell division, when DNA is „swapped” between chromosomes 9 and 22. Part of chromosome 9 goes to 22 and part of 22 goes to 9. […] This new abnormal chromosome is called the Philadelphia chromosome. The Philadelphia chromosome is found in the leukemia cells of almost all patients with CML. […] The swapping of DNA between the chromosomes leads to the formation of a new gene (an oncogene) called BCR-ABL. This gene then produces the BCR-ABL protein, which is the type of protein called a tyrosine kinase. This protein causes CML cells to grow and divide out of control. […] Sometimes people inherit DNA mutations from a parent that greatly increase their risk of getting certain types of cancer. But mutations passed on by parents do not cause CML. DNA changes related to CML occur during the person’s lifetime, rather than having been inherited before birth.

• #9 Chronic myeloid leukemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/chronic-myeloid-leukemia/

  Chronic myeloid leukemia is caused by a rearrangement (translocation) of genetic material between chromosome 9 and chromosome 22. This translocation, written as t(9;22), fuses part of the ABL1 gene from chromosome 9 with part of the BCR gene from chromosome 22, creating an abnormal fusion gene called BCR-ABL1. The abnormal chromosome 22, containing a piece of chromosome 9 and the fusion gene is often referred to as the Philadelphia chromosome (named for where it was first discovered). The translocation is acquired during a person’s lifetime and is present only in abnormal blood cells. This type of genetic change, called a somatic mutation, is not inherited. […] Like the ABL1 protein, the abnormal protein produced from the fusion gene, called BCR-ABL1, can promote cell proliferation and block apoptosis. However, unlike ABL1, it does not require signals in the cell to turn it on. The constantly active BCR-ABL1 protein signals cells to continue dividing abnormally and prevents them from self-destructing, which leads to overproduction of the abnormal cells and, eventually, a shortage of normal blood cells. The presence of the Philadelphia chromosome provides a target for molecular therapies in people with chronic myeloid leukemia.

• #10 Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10084831/

  In CML, there are other types of BCR-ABL1 fusion and breakpoints. For example, p190BCR-ABL1 (e1a2), which encodes a hybrid 190 kDa protein, can be observed in CML, but the frequency is rare. Based on several studies, p190BCR-ABL1 occurs in only 12% of CML patients. […] The process of transformation from chronic CML to the accelerated phase or blast phase is thought to be caused by amplification of the BCR-ABL1 protein and increased activation of the downstream tyrosine kinase pathway, combined with the emergence of additional chromosomal abnormalities (ACAs). Oxidative stress and impaired DNA repair have also been implicated. […] LSCs have a persistent presence, even with tyrosine kinase inhibitor treatment. Thus, patients in remission are not cured and may technically relapse once TKI treatment is stopped. This suggests that there may be BCR-ABL1-independent pathways that maintain the self-renewal of CML LSCs.

• #11 Chronic Myeloid Leukemia: Biology, Diagnosis, and Management | IntechOpen

  https://www.intechopen.com/chapters/84616

  Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm characterized by florid myelo-megakaryocytic proliferation involving peripheral blood, bone marrow, and spleen. These results are due to balanced reciprocal translocation between long arm of chromosome 9 and 22 that produces a truncated chromosome 22 (Philadelphia chromosome) leading to fusion of BCR-ABL1 genes causing enhanced autonomous activation of tyrosine kinase and downstream cellular proliferation pathway. […] The product of such fusion is a 210-kilo Dalton (KD) (p210 BCR-ABL1), which causes ligand-independent activation of receptor tyrosine kinase protein producing downstream activation of intracellular pathways with uncontrolled proliferation of maturing myeloid and megakaryocyte lineage, so characteristic of this entity.

• #12 Chronic Myeloid Leukemia: Biology, Diagnosis, and Management | IntechOpen

  https://www.intechopen.com/chapters/84616

  The p210 KD protein results in dysregulated tyrosine kinase expression and ligand-independent activation of the downstream intracellular pathways. Major mechanism that has been postulated in pathogenesis of CML includes: a) adhesion to stromal cells and extracellular matrix (ECM), b) constant state of mitogenic activation, c) inhibition of apoptosis, and d) proteasomal degradation of BCR-ABL1 inhibitory proteins. […] Moreover, BCR-ABL1 fusion activates the PI3-AKT pathway, which in turn phosphorylates the FOXO transcription factor causing cell cycle arrest and leukemogenesis and along with TGF- signaling pathway, it has a significant role in survival of leukemic stem cells. Besides these, activation of transcriptional factors such as STAT1 and STAT5 (signal transducer and activation of transcription) contributes to survival advantage and cytokine independency. Other pathways that cause disruption of key cellular process include RAS-mitogen-activated protein kinase (RAS-MAPK pathway) leading to increased proliferation, MYC overexpression, and alteration of Hedgehog signaling pathway.

• #13 Chronic Myeloid Leukemia: The Complexities of Pathogenesis, Diagnosis, and Modern Therapeutic Approaches | Open Access Journals

  https://www.rroij.com/open-access/chronic-myeloid-leukemia-the-complexities-of-pathogenesis-diagnosis-and-modern-therapeutic-approaches.php?aid=93602

  The BCR-ABL1 fusion protein has constitutive tyrosine kinase activity. This means it can continuously activate signaling pathways that promote cell growth and inhibit apoptosis (cell death). This unchecked kinase activity is a key driver of CML pathogenesis, as it leads to uncontrolled proliferation of myeloid cells. […] BCR-ABL1 activates various downstream molecular pathways, including the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways. These pathways play essential roles in cell survival, growth, and differentiation. Their dysregulation contributes to the excessive production of myeloid cells and the failure of normal regulation mechanisms. […] CML originates in hematopoietic stem cells, which give rise to all blood cell types. The presence of the BCR-ABL1 fusion gene in these stem cells ensures that the abnormality is perpetuated as these cells differentiate into mature blood cells, including granulocytes. This leads to an overproduction of granulocytes, a hallmark of CML.

• #14 Chronic myelogenous leukemia, a still unsolved problem: pitfalls and n | DDDT

  https://www.dovepress.com/chronic-myelogenous-leukemia-a-still-unsolved-problem-pitfalls-and-new-peer-reviewed-fulltext-article-DDDT

  Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. At the molecular level, the disorder results from t(9;22)(q34;q11) reciprocal translocation between chromosomes, which leads to the formation of an oncogenic BCR-ABL gene fusion. […] Therefore, it is accepted that acquisition of the BCR-ABL oncogene (especially the p210 BCR-ABL form) is the initiating step in the development of CML. The acquisition of the BCR-ABL gene initially occurs in a single pluripotent HSC that gains a proliferative advantage and/or aberrant differentiation capacity over its normal counterparts, giving rise to the expanded myeloid compartment. […] This results in autophosphorylation of p210 BCR-ABL on the Y177 tyrosine residue and leads to phosphorylation of many downstream targets. Activation of various signaling pathways such as Ras/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), or signal transducer and activator of transcription 5 (STAT5) by BCR-ABL kinase leads to tumor transformation in conjunction with dysfunction of underlying cellular processes associated with the control of proliferation, differentiation, and survival.

• #15 Chronic myelogenous leukemia, a still unsolved problem: pitfalls and n | DDDT

  https://www.dovepress.com/chronic-myelogenous-leukemia-a-still-unsolved-problem-pitfalls-and-new-peer-reviewed-fulltext-article-DDDT

  The major cellular events initiated by BCR-ABL kinase important in the malignant transformation include altered adhesion to stroma cells and the extracellular matrix, constitutively active mitogenic signaling, reduced apoptosis, and altered DNA repair mechanisms. However, some new factors such as elevated levels of reactive oxygen species (ROS) and autophagy seem to play important roles in CML development and progression. […] Neoplastic transformation, which occurs through the BCR-ABL, is associated with constitutive activation of the Ras/MAPK signaling pathway. […] An active Akt kinase promotes cell survival by phosphorylation of proapoptotic Bad protein at serine 136. […] Pleiotropic action of BCR-ABL kinase on the PI3K/AKT, MAPK, and other signaling pathways results in changes in ROS regulation in HSC.

• #16

• #17 Chronic myeloid leukemia stem cells: targeting therapeutic implications | Stem Cell Research & Therapy | Full Text

  https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02659-1

  In other words, it is possible to develop the combination therapy of TKs with drugs targeting genes or molecules more specifically, which is required for survival mechanisms of CML LSCs, while sparing normal HSCs for clinical benefits along with TKIs. […] The presence of fusion oncogene BCR-ABL1 and generating a 210 KD chimeric oncoprotein (P210) with the constitutive activity of tyrosine kinase leads to clonal expansion of hematopoietic stem cell (HSC) and the pathogenesis of CML. […] BCR-ABL1 contributes to CML leukemia stem cells (LSCs), identified by survival promotion, the capacity of self-renewal, and differentiation to aberrant hematopoietic subsets and resistance to apoptosis through the activation of various signaling molecules and pathways in downstream of the BCR-ABL protein, to regulate leukemogenesis.

• #18 Chronic myeloid leukemia stem cells: targeting therapeutic implications | Stem Cell Research & Therapy | Full Text

  https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02659-1

  This review underlines the current known characteristics of CML LSCs besides possible mechanisms and pathways that lead to survival and resistance to targeted multimodal therapies that might help developing new drugs and treatment options, since current therapeutic strategies often represent limitations and failures. […] Over the total genetic alterations of HSCs into CML LSCs, activation of various signaling pathways leads to CML progression as an LSC-derived disease, along with dysfunction of underlying cellular processes. […] The generation of BCR-ABL fusion gene in CML LSCs may have a role in a variety of biological processes, notably cell proliferation, differentiation, and apoptosis by encoding a constitutively activating tyrosine kinase as important mediator of signaling cascades such as RAS/mitogen-activated protein kinase (MAPK), PI3K/Akt/FOXO axis, WNT signaling, and JAK2/STAT3,5 signaling, which are implicated in the maintenance and survival of CML LSCs. […] As a result of the signaling pathways upregulation, the level of ROS and genomic instability increased that have a potential to create other mutations and chromosomal abnormalities, following the advancement of CML from the CP to the BP.

• #19 Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

  https://www.mdpi.com/1422-0067/20/24/6141

  BCR-ABL1 is necessary for malignant transformation but not sufficient to sustain BP. […] The frequency of numerical and structural chromosomal changes results to be much higher in BP-CML compared with CP-CML. […] BCR-ABL1 is considered a direct cause of genomic instability since its expression and activity are responsible for the generation of reactive oxygen species (ROS), disruption of DNA repair pathways and inhibition of DNA damage-induced apoptosis that may result in aneuploidy, chromosomal alterations, DNA deletions and insertions, and point mutations. […] BCR-ABL1 kinase activity has been found to elevate intracellular ROS levels, and this was markedly more evident in BP CML cells, exhibiting higher BCR-ABL1 levels, than in CP CML cells. […] The mismatch repair (MMR) system has the role to maintain genomic stability by detecting misincorporated nucleotides, by acting an excision repair before point mutations emerge and by inducing cell apoptosis in case of unrepairable DNA damage.

• #20 Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

  https://www.mdpi.com/2072-6694/13/19/4820

  The DNA damage response (DDR) deregulation that leads to DNA damage and genomic instability has been implicated in the CML evolution, leading to TKI resistance and disease transition from CP-CML to more malignant stages. […] The BCR-ABL1 oncoprotein is responsible for the genomic instability observed in CML since its activity generates reactive oxygen species (ROS), disrupts the DDR pathways activating error-prone DNA repair, induces replication stress and centrosomal dysfunction, and inhibits apoptosis resulting from different DNA damage-induced lesions. […] Treatment efficacy is highly dependent on the access of the drug to its molecular target. For targeting BCR-ABL1 (a non-receptor tyrosine kinase), it is critical for TKIs to reach the inside of CML cells at adequate pharmacological concentrations to achieve therapeutic clinical outcomes.

• #21 Chronic myelogenous leukemia, a still unsolved problem: pitfalls and n | DDDT

  https://www.dovepress.com/chronic-myelogenous-leukemia-a-still-unsolved-problem-pitfalls-and-new-peer-reviewed-fulltext-article-DDDT

  Genomic instability acts as a mutator, ie, this has a potential to create other mutations. […] However, some lines of evidence show that in CML cells the key players of NHEJ, Artemis, and DNA ligase IV are downregulated. […] This suggests that as long as the a-NHEJ pathway contributes to ROS-induced DSB repair the genomic instability increases, leading to the progression of the disease from the chronic to the BP. […] The pivotal deregulated control mechanisms of cells in cancer development are apoptosis and autophagy processes. […] In CML cells, autophagy is downregulated by constitutively activated BCR-ABL kinase. […] The mechanism responsible for this inhibition correlates with upregulation of the mTOR pathway. […] This means that the regulation of mTORC1 kinase activity by BCR-ABL occurs on both the transcriptional and the protein level. […] The results selected from many of the papers published in recent years seem to present promising compounds against CML and carry significant meaning in understanding the mechanisms of CML development and progression as well as the possibilities for its treatment.

• #22 Pathogenesis and treatment of Chronic Myeloid Leukemia | PPT

  https://www.slideshare.net/slideshow/pathogenesis-and-treatment-of-chronic-myeloid-leukemia/76636521

  Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the Philadelphia chromosome and BCR-ABL fusion gene. […] The natural history involves chronic, accelerated, and blast crisis phases if untreated. […] Philadelphia Chromosome Translocation in CML Results in BCR-ABL Oncogene Gene Transcription Inhibits Apoptosis Excessive proliferation Cytoskeletal organization Degradation of inhibitory proteins. […] CML stem cell hypothesis STIM and TWISTER trial Immunophenotype: Lin-ve, CD 34+ve, CD 38-ve, CD 90+ve Phonotypically and functionally similar to normal HSCs. […] Signal Transduction Pathways Involved JAK-STAT pathway PI3K/AKT/mTOR pathway WNT/-catenin pathway Hedgehog pathway Epigenetic regulators. […] CML progresses through chronic, accelerated and blast crisis phases as additional genetic mutations accumulate.

• #23

  https://www.jci.org/articles/view/41246

  The BCR-ABL1 oncoprotein transforms pluripotent HSCs and initiates chronic myeloid leukemia (CML). […] LSCs or their progeny can acquire additional genetic and/or epigenetic changes that cause the leukemia to transform from CP to a more advanced phase, which has been subclassified as either accelerated phase or blastic phase disease. […] The biological basis of BP is poorly understood. […] These findings lend support to the notion that the BCR-ABL1 oncogene arises in a primitive cell, namely a leukemia stem cell (LSC), not yet committed to either myeloid or lymphoid differentiation. […] Here, we discuss genetic and epigenetic mechanisms leading to the transition of CML-CP into CML-BP and propose some novel therapeutic modalities that might prevent malignant progression. […] The genetic lesions observed in CML-BP patients in the past and now since the introduction of TKIs mostly include the presence of additional chromosomes, gene deletions, gene insertions, and/or point mutations (including BCR-ABL1 mutations).

• #24 Chronic myeloid leukemia stem cells: targeting therapeutic implications | Stem Cell Research & Therapy | Full Text

  https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02659-1

  Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm driven by BCR-ABL1 oncoprotein, which plays a pivotal role in CML pathology, diagnosis, and treatment as confirmed by the success of tyrosine kinase inhibitor (TKI) therapy. […] Despite advances in the development of more potent tyrosine kinase inhibitors, some mechanisms particularly in terms of CML leukemic stem cell (CML LSC) lead to intrinsic or acquired therapy resistance, relapse, and disease progression. […] In fact, the maintenance CML LSCs in patients who are resistance to TKI therapy indicates the role of CML LSCs in resistance to therapy through survival mechanisms that are not completely dependent on BCR-ABL activity. […] Targeting therapeutic approaches aim to eradicate CML LSCs through characterization and targeting genetic alteration and molecular pathways involving in CML LSC survival in a favorable leukemic microenvironment and resistance to apoptosis, with the hope of providing a functional cure.

• #25 Chronic myeloid leukemia stem cells: targeting therapeutic implications | Stem Cell Research & Therapy | Full Text

  https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02659-1

  The LSCs can be also a persistent problem of CML patients since regardless of BCR-ABL kinase activation, they alter the relationship with bone marrow niche and leave the quiescence state and reach to proliferation state via intracellular signaling changes and suppressive cytokines secretion that can disrupt metabolic processes, prepare an anti-apoptotic microenvironment, and dysregulate immunological activities. […] However, the major barrier against treatment of CML via the family of TKIs is primary and acquired resistance resulted from the accumulation of LSCs with a high heterogeneity in the blood and BM. […] In brief, CML stem cells can be either expressive or independent of BCR-ABL1 and represent TKI-resistant. […] Therefore, the discovery of uncertain CML LSCs resistance mechanisms can be a great target to facilitate the eradication of these cells.

• #26 Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1567

  Chronic myelogenous leukaemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. Clinical and laboratory studies indicate that the fusion protein BCRABL is essential for initiation, maintenance and progression of CML, yet the transformation of CML from chronic phase to blast phase requires additional genetic and/or epigenetic abnormalities. […] Transgenic expression of BCRABL in mice leads to a myeloproliferative disorder that resembles the chronic phase of CML in patients. The ABL tyrosine-kinase activity is necessary but not sufficient to induce CML-like disease in mice. So, additional activities of BCRABL, beyond its kinase activity, are important for leukaemogenesis. […] BCRABL also interacts with oncogenic transcription factors to induce a form of acute myelogenous leukaemia that resembles the blast phase of CML, indicating that disease progression involves cooperation between BCRABL and mutations that disrupt haematopoietic gene transcription. […] CML progenitor cells seem to be refractory to imatinib therapy, indicating that the biology of haematopoietic stem/progenitor cells and tumour microenvironment are likely to contribute to the disease development and maintenance.

• #27 Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

  https://www.mdpi.com/2072-6694/13/19/4820

  The persistence of leukemic stem cells (LSCs) and LSC-like phenotype based on BCR-ABL1 protein suppression have also been reported as a main TKI resistance mechanisms. […] Several mechanisms are associated with TKI resistance, including BCR-ABL1 mutations and overexpression, abnormal activity of drug transporters, activation of alternative signaling pathways, DNA repair, and genomic instability, epigenetic dysfunction, leukemia stem cell (LSC) persistence, and dysfunction of the immune system. […] The effectiveness of TKI treatment is highly dependent on proper BCR-ABL1–drug interaction, and the most studied mechanisms are those responsible for the reactivation of BCR-ABL1 kinase activity. Overexpression of BCR-ABL1 and mutations on the fusion gene that impair the binding of TKI to targeted kinase may lead to resistance and are classified as BCR-ABL1 dependent mechanisms.

• #28 Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

  https://www.mdpi.com/2072-6694/13/19/4820

  To overcome the inhibition of BCR-ABL1, CML cells may activate alternative signaling pathways to compensate the loss of BCR-ABL1 kinase activity. […] The LSCs display high resistance to TKI showing heterogenous adaptations including a modified transcriptome, genome, and epigenome. […] There is now ample evidence that epigenetic dysregulation contributes to leukemic stem cell generation, maintenance, and progression in CML. […] In CML, as described in other neoplasias, the leukemic cells become progressively independent of physiological control of BMM. […] The immune system is an essential player within the BMM, and expression of specific immune cells might dictate successful TKI responses. […] The molecular mechanisms behind TKI resistance are multiple, ranging from changes in the molecular drug target itself, to mechanisms that alter drug concentration or modify leukemic cells signaling network. […] The point mutations in BCR-ABL1 chimeric protein, including the gatekeeper T315I mutation, are the principal cause for the development of resistance to TKIs. However, other mechanisms are also involved in the failure of TKI therapy.

• #29 Chronic Myeloid Leukemia: The Complexities of Pathogenesis, Diagnosis, and Modern Therapeutic Approaches | Open Access Journals

  https://www.rroij.com/open-access/chronic-myeloid-leukemia-the-complexities-of-pathogenesis-diagnosis-and-modern-therapeutic-approaches.php?aid=93602

  CML typically progresses through three clinical phases: chronic, accelerated, and blast phase. The chronic phase is often asymptomatic or mild, but as the disease advances, it becomes more aggressive and difficult to treat. The blast phase is characterized by the proliferation of immature, blast cells and is often fatal if not treated.

• #30 Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10084831/

  The goal of therapy in CML is to achieve a hematological response, a cytogenetic response, and a long-term major molecular response. A complete hematological response (CHR) is defined as a normal leukocyte count, a normal platelet level, a normal differential result, and the disappearance of CML symptoms. […] Many advances have been made in improving our understanding of the pathophysiological processes of CML. However, the etiology of the Philadelphia chromosome and mechanisms of LSC persistence are still under investigation. Somatic mutations and additional chromosomal abnormalities are associated with CML progression into blast phase.

• #31 Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

  https://www.mdpi.com/1422-0067/20/24/6141

  Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. […] Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. […] The BCR-ABL1 oncogene arises in a primitive cell named leukemia stem cell (LSC), not yet committed to either myeloid or lymphoid differentiation.

• #32

  https://www.jci.org/articles/view/41246

  Thus, it is highly plausible that unrestrained and increasing BCR-ABL1 activity promotes and/or contributes to clonal evolution, thereby leading to CML-BP. […] Because there is a direct correlation between levels of BCR-ABL1, the frequency of clinically relevant BCR-ABL1 mutations, and the differentiation arrest of myeloid progenitors, it is likely that disease progression is triggered by the right combinations of genetic and epigenetic abnormalities. […] Genomic instability usually results from an aberrant cellular response to enhanced DNA damage. […] Altogether, we postulate that elevated levels of DNA damage combined with unfaithful/inefficient DNA repair may generate mutations and chromosomal aberrations in CML-CP LSCs and/or LPCs, causing resistance to TKIs and progression toward CML-BP.

• #33 Chronic myeloid leukemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/chronic-myeloid-leukemia/

  Researchers believe that additional genetic changes play a role in the progression of the chronic phase of chronic myeloid leukemia to the accelerated phase and blast crisis. The most common genetic changes associated with progression to blast crisis include an extra copy of chromosome 8 (trisomy 8), an abnormality of chromosome 17 known as isochromosome 17, and an extra copy (duplication) of the Philadelphia chromosome. When these somatic mutations occur in cells with the Philadelphia chromosome, they likely further promote uncontrolled cell proliferation.

• #34 Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

  https://www.mdpi.com/1422-0067/20/24/6141

  The presence of ACAs can be observed at diagnosis in approximately 5% or less of CP CML patients as demonstrated by several studies. […] The most frequently mutated gene in CML is BCR-ABL1 itself. Point mutations within the ABL1 KD may indeed be selected during TKI therapy, leading to treatment failure. […] In lymphoid BP, one of the most frequent abnormalities is represented by monoallelic or biallelic deletions of the CDKN2A/B locus, encoding the tumor suppressors and cell cycle regulators INK4A, INK4B, and ARF. […] The recent advent of high throughput technologies like DNA microarrays and next generation sequencing (NGS) has contributed to further unravel the genetic/genomic complexity of BP cells. […] In BP-CML, loss of function of key tumor suppressors may also be mediated by events not acting at the genomic level.

• #35 Cytogenetics of Chronic Myelogenous Leukemia

  https://www.uspharmacist.com/article/cytogenetics-of-chronic-myelogenous-leukemia

  Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by a translocation between chromosomes 9 and 22, forming the Philadelphia (Ph) chromosome. […] Chronic myelogenous leukemia (CML) is a myeloproliferative disorder initiated by a genetic translocation within a pluripotent stem cell. This malignant transformation leads to unregulated growth and accumulation of myeloid cells. […] The hybrid BCR-ABL tyrosine kinase is constitutively active, dysregulating downstream pathways driving malignant cell proliferation and resistance to apoptosis. […] BCR-ABL down regulates the DNA repair process, enabling additional mutations. […] The most frequently seen chromosomal changes include trisomy 8, isochrome 17, duplicate Ph chromosome, loss of 17p and BCR-ABL1. […] Mutations in the BCR-ABL gene can occur as well. Determination of the specific mutation is clinically important as it may dictate a change in therapy. Changes in the structure of BCR-ABL can interfere with drugs designed to inhibit downstream signaling. Over 40 different mutations involving amino acid substitutions have been reported, most often found in the area where ATP binds to BCR-ABL.

• #36 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.

• #37 Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis – UpToDate

  https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-chronic-myeloid-leukemia

  Chronic myeloid leukemia (CML; previously called chronic myelogenous leukemia, chronic myelocytic leukemia, or chronic granulocytic leukemia) is a myeloproliferative neoplasm that manifests uncontrolled proliferation of mature and maturing granulocytes in blood and bone marrow. CML is characterized by t(9;22), a reciprocal translocation of chromosomes 9 and 22, which results in an abnormally short chromosome 22 known as the Philadelphia (Ph) chromosome. The chromosomal translocation generates the BCR::ABL1 fusion gene, which is translated into a constitutively active tyrosine kinase protein. […] BCR::ABL1 is exquisitely sensitive to BCR::ABL1 tyrosine kinase inhibitors (TKIs), and they effectively control CML in most patients. TKIs have improved outcomes so that the survival of patients with CML is now comparable to that of the general population. […] This topic discusses pathogenesis, clinical presentation, and diagnosis of CML.

• #38 Pathogenesis of chronic myeloid leukemia – from gene to targeted therapy | Å»ołnierowicz | Hematology in Clinical Practice

  https://journals.viamedica.pl/hematology_in_clinical_practice/article/view/15743?fbclid=IwAR3GG6PYlOCxdAIYhPN7fSdx5r10F3wwh3LZt30tAgD0PpN4wAYvlDHg7to

  The occurrence of chronic myeloid leukemia (CML) is related to the appearance of reciprocal chromosomal translocation (9;22)(q34;q11). As a result of translocation between chromosomes 9 and 22, shortened chromosome 22 – Philadelphia (Ph) chromosome arises, coding for constitutively active protein tyrosine kinase, BCR-ABL1. The subsequent deregulation of the ABL1 kinase activity in cells leads to enhanced proliferation, resistance to apoptosis and altered adhesion. The discovery of imatinib, a relatively specific tyrosine kinase inhibitor, including ABL1 and BCR-ABL1 kinases, was a breakthrough in CML treatment. Imatinib functions by binding to the active site of ABL1 kinase in an inactive conformation, thus blocking the ATP binding site crucial for enzyme activity. Although imatinib has revolutionized CML therapy, appearance of resistance to this inhibitor leads to CML progression. In case of imatinib-resistance, several possible strategies exist for the management of the disease, which include increasing the dose of imatinib, changing therapy to the 2nd generation tyrosine kinase inhibitors or allogeneic hematopoietic stem cell transplantation.

• #39 Chronic Myelogenous Leukemia (CML) – Leukemias – Pathology – Picmonic for Medicine

  https://www.picmonic.com/pathways/medicine/courses/standard/pathology-196/leukemias-39333/chronic-myelogenous-leukemia-cml_389

  Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the presence of a chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9 caused by (9;22) translocation. This is called a Philadelphia chromosome and this gene synthesizes a constitutively active BCR-ABL tyrosine kinase. […] CML is characterized by a constitutively active BCR-ABL tyrosine kinase. Activation of this kinase induces pro-growth and pro-survival pathway that are normally turned on by hematopoietic growth factors. For unknown reasons, the BCR-ABL tyrosine kinase preferentially stimulates the proliferation of granulocytic and megakaryocytic progenitors and causes the abnormal release of immature granulocytic forms from the bone marrow into the blood. […] Understanding the molecular pathogenesis of CML has led to the use of the drug imatinib, which is a specific BCR-ABL inhibitor. Imatinib results in sustained hematologic remission in about 90% of patients with markedly decreased number of BCR-ABL positive cells in the marrow.

• #40 Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

  https://www.mdpi.com/2072-6694/13/19/4820

  Chronic myeloid leukemia (CML) is a myeloproliferative neoplasia associated with a molecular alteration, the fusion gene BCR-ABL1, that encodes the tyrosine kinase oncoprotein BCR-ABL1. This led to the development of tyrosine kinase inhibitors (TKI), with Imatinib being the first TKI approved. […] Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. […] In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms.

• #41 Cytogenetics of Chronic Myelogenous Leukemia

  https://www.uspharmacist.com/article/cytogenetics-of-chronic-myelogenous-leukemia

  The „gatekeeper” mutation T315I interferes with imatinib binding, predicting resistance to imatinib and other tyrosine kinase inhibitors (i.e., dasatinib and nilotinib). […] The presence of a specific genetic abnormality, targeted drug therapies, and the availability of sensitive and specific methods to monitor response make CML a unique disease amongst hematologic malignancies. Recent advances allow clinicians to make adjustments to therapy often before overt changes in the clinical course occur. Notably, knowledge of the molecular pathways and events driving disease progression are leading to the development of novel drug therapies.

• #42 Chronic myeloid leukemia: cytogenetics and molecular biology’s part in the comprehension and management of the pathology and treatment evolution | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-022-00248-2

  There are four main mechanisms involved in the induction of oncogenesis. These mechanisms are implicated in the continuous activation of the tyrosine kinase receptor (TKR) in CML: (1) gain-of-function mutations, (2) genome amplification, (3) chromosome aberrations and (4) autocrine activation by CML stem cells. BCR-ABL1 activates a variety of signaling pathways leading to cell proliferation, promotion of survival, inhibition of apoptosis, alteration of cell adhesion to the extracellular matrix and leukemic cells capability of self-renewal. […] Point mutations in the ABL1 domain are found in 50% of patients resistant to imatinib and lead to a loss of affinity between the TKI and its binding site in the ABL1 domain. More than 80 amino acid substitutions have been reported in association with resistance to imatinib.

• #43 Signaling pathways involved in chronic myeloid leukemia pathogenesis: the importance of targeting Musashi2-Numb signaling to eradicate leukemia stem cells

  https://ijbms.mums.ac.ir/article_12723.html

  Chronic myeloid leukemia (CML) is a myeloid clonal proliferation disease defining by the presence of the Philadelphia chromosome that shows the movement of BCR-ABL1. […] The main problem is stem cells resistance to Imatinib therapy. Therefore, the identification and control of downstream molecules/ signaling route of the BCR-ABL1 that are involved in the survival and self-renewal of leukemia stem cells can be an effective treatment strategy to eliminate leukemia stem cells, which supposed to be cured by Musashi2-Numb signaling pathway. […] The control of molecules /pathways downstream of the BCR-ABL1 and targeting Musashi2-Numb can be an effective therapeutic strategy for treatment of chronic leukemia stem cells.

• #44

  https://www.omim.org/entry/608232

  A number sign (#) is used with this entry because chronic myeloid leukemia is most frequently caused by a translocation between chromosomes 22 and 9, creating a BCR/ABL fusion gene encoding a tyrosine kinase (see 151410). […] Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B lymphoid, and sometimes T lymphoid cells, but not marrow fibroblasts. […] Along with clinical aspects of chronic myeloid leukemia, Sawyers (1999) reviewed the molecular aspects of its pathogenesis. […] Goldman and Melo (2003) summarized advances in knowledge related to the pathogenesis of CML. […] Ito et al. (2010) used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signaling axis. Specifically, Ito et al. (2010) found that the chronic phase of CML is marked by high levels of Numb (603728) expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, Ito et al. (2010) showed that Nup98-Hoxa9 (see 601021), an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi-2 (MSI2; 607897), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally, Ito et al. (2010) found that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poor prognosis.

• #45

  https://www.omim.org/entry/608232

  Abraham et al. (2016) used proteomics, transcriptomics, and network analyses to show that in human leukemic stem cells (LScs), aberrantly expressed proteins in both imatinib-responder and -nonresponder patients are modulated in concert with p53 (191170) and c-MYC (190080) regulation. Perturbation of both p53 and c-MYC, and not BCR-ABL itself, leads to synergistic cell kill, differentiation, and near elimination of transplantable human LSCs in mice, while sparing normal hematopoietic stem cells. Abraham et al. (2016) concluded that this unbiased systems approach targeting connected nodes exemplified a novel precision medicine strategy providing evidence that LSCs can be eradicated.

• #46

  https://www.jci.org/articles/view/129061

  Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. […] We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. […] Hematopoietic cell-specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. […] Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. […] Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.

• #47

  https://www.jci.org/articles/view/129061

  Here, we show that cell-autonomous expression of a heparin-binding growth factor, pleiotrophin (PTN), is necessary for CML pathogenesis and initiation of CML in transplanted mice. […] Antibody-mediated inhibition of PTN suppresses human CML growth in vitro and in vivo, suggesting that PTN is an attractive therapeutic target in human CML. […] PTN is necessary for CML pathogenesis in BCR/ABL-expressing mice. […] These data suggest that deletion of PTN substantially decreased CML stem cells capable of reconstituting CML in transplanted mice. […] PTN deletion impairs CML stem cell repopulating capacity. […] Our data suggest that PTN deletion abrogates CML disease initiation in transplanted mice, a hallmark of CML stem cell function. […] These results suggest that PTN is a potentially important therapeutic target for human CML and AML.

• #48 Chronic myeloid leukemia – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/chronic-myeloid-leukemia/

  Additional chromosomal changes and mutations of tumor suppressor genes and oncogenes (p53, Rb1, or Ras), which emerge during the course of the disease, are responsible for the progression from chronic to accelerated phase and, ultimately, the transition to acute leukemia. […] The presence of additional mutations is associated with more advanced stages of CML (i.e., AP-CML or BP-CML) and can cause resistance to targeted therapy. […] Identification of the BCR-ABL1 fusion gene is the hallmark of CML and confirms the diagnosis. […] Selective inhibition of tyrosine kinase (e.g., by blocking its ATP binding site): inhibits tyrosine phosphorylation of downstream signaling proteins (no phosphate transfer from ATP to tyrosine residues). Disruption of the BCR-ABL1 pathway: inhibits proliferation and induces apoptosis in BCR-ABL1-positive cells.

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