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 p210BCR-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 (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).

• #3 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. […] The mechanism of Philadelphia chromosome formation and the time from the formation of the chromosome to the occurrence of clinical symptoms of CML are still not known with certainty.

• #4 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 p210BCR-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).

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

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

  Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. […] CML is one of the few cancers known to be caused by a single, specific genetic mutation. More than 90% of cases result from a cytogenetic aberration known as the Philadelphia chromosome. […] CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)]. The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph1) chromosome.

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

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

  Normal human cells grow and function based mainly on the information contained in each cell’s chromosomes. […] 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. […] This is known as a translocation and it makes a chromosome 22 that’s shorter than normal. 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.

• #7 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 p210BCR-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).

• #8 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.

• #9 Chronic Myelogenous Leukemia | CML | MedlinePlus

  https://medlineplus.gov/chronicmyeloidleukemia.html

  Chronic myeloid leukemia (CML) is a type of chronic leukemia. „Chronic” means that the leukemia usually gets worse slowly. In CML, the bone marrow makes abnormal granulocytes (a type of white blood cell). These abnormal cells are also called blasts. When the abnormal cells crowd out the healthy cells, it can lead to infection, anemia, and easy bleeding. The abnormal cells can also spread outside the blood to other parts of the body. […] Most people with CML have a genetic change called the Philadelphia chromosome. It’s called that because researchers in Philadelphia discovered it. People normally have 23 pairs of chromosomes in each cell. These chromosomes contain your DNA (genetic material). In CML, part of the DNA from one chromosome moves to another chromosome. It combines with some DNA there, which creates a new gene called BCR-ABL. This gene causes your bone marrow to make an abnormal protein. This protein allows the leukemia cells to grow out of control.

• #10 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. […] The mechanism of Philadelphia chromosome formation and the time from the formation of the chromosome to the occurrence of clinical symptoms of CML are still not known with certainty.

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

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

  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. […] 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. […] 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).

• #12 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.

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

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

  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. […] 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. […] 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).

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

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

  Normal human cells grow and function based mainly on the information contained in each cell’s chromosomes. […] 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. […] This is known as a translocation and it makes a chromosome 22 that’s shorter than normal. 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.

• #15 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).

• #16 The importance of personalized medicine in chronic myeloid leukemia management: a narrative review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-023-00411-3

  Despite acceptable results of TKIs in the treatment of CML patients, tyrosine kinase inhibitor (TKI) resistance is the main challenge among these patients. […] Chronic myeloid leukemia is caused by chromosomal translocation of t(9;22), which results in the Ph+ chromosome formation, and BCR-ABL1 gene manufacturing. […] BCR-ABL plays a critical role in producing the disease by tyrosine kinase activity. […] P210BCR-ABL leads to phosphorylation of various cellular substrates, as a result of activating several downstream signal-transduction cascades such as RAS/MAPK, c-Casitas B lineage lymphoma (c-CBL), PI3- kinase, and Chicken Tumor 10 Regulator of Kinases-like protein (CRKL), Src pathway, and JAK-STAT by p210 BCR-ABL cause the malignant form of the cells. […] Thereby p210 can control cell differentiation and proliferation.

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

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

  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. […] 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. […] 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).

• #18 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 p210BCR-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).

• #19 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.

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

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

  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.

• #21 Chronic Myeloid Leukemia | IntechOpen

  https://www.intechopen.com/chapters/70989

  The BCR-ABL fusion protein acts as an oncoprotein by activating several signaling pathways that lead to transformation. […] Activation of these signaling pathways leads to deregulation of cellular processes such as proliferation, differentiation, DNA repair, decreased adhesion of leukemic cells to bone marrow stroma, and reduced apoptotic response to mutagenic stimulation, leading to uncontrolled clonal proliferation.

• #22 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).

• #23 Chronic myelogenous leukemia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/chronic-myelogenous-leukemia/symptoms-causes/syc-20352417

  Chronic myelogenous leukemia happens when something causes changes to the bone marrow cells. It’s not clear what starts this process. However, doctors have discovered how it progresses into chronic myelogenous leukemia. […] Most people with chronic myelogenous leukemia have a chromosome called the Philadelphia chromosome inside their blood cells. Typical cells each contain 23 pairs of chromosomes that are made of DNA. DNA holds the instructions for every cell in the body. The Philadelphia chromosome forms when chromosome 9 and chromosome 22 break and exchange parts. This creates a short chromosome 22 and a new combination of instructions for the cells. These new instructions can lead to the development of chronic myelogenous leukemia. […] Genes from chromosome 9 combine with genes from chromosome 22 to create a new gene called BCR-ABL. The BCR-ABL gene tells the blood cells to produce too much of a protein called tyrosine kinase. Tyrosine kinase promotes cancer by allowing certain blood cells to grow out of control.

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

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

  Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. […] CML is one of the few cancers known to be caused by a single, specific genetic mutation. More than 90% of cases result from a cytogenetic aberration known as the Philadelphia chromosome. […] CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)]. The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph1) chromosome.

• #25 Chronic myeloid leukemia – Knowledge @ AMBOSS

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

  Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm involving hematopoietic stem cells that results in overexpression of cells of myeloid lineage, especially granulocytes. It is caused by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome, which contains the BCR-ABL1 fusion gene. The BCR-ABL1 fusion gene encodes a hybrid tyrosine kinase with increased enzymatic activity that leads to unregulated proliferation of hematopoietic stem cells. […] Reciprocal translocation between chromosome 9 and chromosome 22 formation of the Philadelphia chromosome t(9;22) fusion of the ABL1 gene (chromosome 9) with the BCR gene (chromosome 22) formation of the BCR-ABL gene encodes a BCR-ABL non-receptor tyrosine kinase with increased enzyme activity.

• #26 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. […] The mechanism of Philadelphia chromosome formation and the time from the formation of the chromosome to the occurrence of clinical symptoms of CML are still not known with certainty.

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

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

  The presence of ACAs in the early stages appears to be associated with disease progression in CML. […] The malignant HSCs, termed leukemia stem cells (LSCs), provide a reservoir of self-replenishing leukemia cells. Thus, to completely eradicate CML, LSCs ideally must be targeted and removed to prevent relapse. […] 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. […] The antiproliferative effects of TKIs on LSCs have been shown to be strong; however, the effect on apoptosis is weaker. The reason for this is that quiescent LSCs are resistant to apoptosis due to TKIs. A further problem is associated with the BCR-ABL-independent pathway, which maintains the survival of CML stem cells.

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

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

  The presence of ACAs in the early stages appears to be associated with disease progression in CML. […] The malignant HSCs, termed leukemia stem cells (LSCs), provide a reservoir of self-replenishing leukemia cells. Thus, to completely eradicate CML, LSCs ideally must be targeted and removed to prevent relapse. […] 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. […] The antiproliferative effects of TKIs on LSCs have been shown to be strong; however, the effect on apoptosis is weaker. The reason for this is that quiescent LSCs are resistant to apoptosis due to TKIs. A further problem is associated with the BCR-ABL-independent pathway, which maintains the survival of CML stem cells.

• #29 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.

• #30 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.

• #31 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. […] Several factors are suggested to be important in the maintenance of CML LSCs through either the direct activation by kinase activity of BCR-ABL or independent of BCR-ABL kinase activity. […] The other required factors in survival of CML LSCs are bone marrow resident cells and the support of LSCs in localization to the bone marrow niche.

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

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

  The presence of ACAs in the early stages appears to be associated with disease progression in CML. […] The malignant HSCs, termed leukemia stem cells (LSCs), provide a reservoir of self-replenishing leukemia cells. Thus, to completely eradicate CML, LSCs ideally must be targeted and removed to prevent relapse. […] 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. […] The antiproliferative effects of TKIs on LSCs have been shown to be strong; however, the effect on apoptosis is weaker. The reason for this is that quiescent LSCs are resistant to apoptosis due to TKIs. A further problem is associated with the BCR-ABL-independent pathway, which maintains the survival of CML stem cells.

• #33 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. […] The mechanism of Philadelphia chromosome formation and the time from the formation of the chromosome to the occurrence of clinical symptoms of CML are still not known with certainty.

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

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

  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. […] 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. […] 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).

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

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

  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. […] 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. […] 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).

• #36

  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. […] 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).

• #37 KEGG DISEASE: Chronic myeloid leukemia

  https://www.genome.jp/dbget-bin/www_bget?ds:H00004

  Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell. […] On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. The BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. […] While fusion of c-ABL and BCR is believed to be the primary cause of the chronic phase of CML, progression to blast crisis requires other molecular changes. Common secondary abnormalities include mutations in TP53, RB, and p16/INK4A, or overexpression of genes such as EVI1.

• #38

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

  The frequency of additional chromosomal abnormalities is approximately 7% in CML-CP and increases to 40%70% in the advanced phases of disease, as evaluated by standard cytogenetic analysis. […] These aberrations involve acquisition of major alterations, such as the acquisition of additional chromosomes (e.g., +Ph, +8, +19); the acquisition of isochromosome i(17q); the acquisition of t(1;17), which is associated with loss of p53; the acquisition of t(1;21), which affects RUNX1; the acquisition of t(3;21), which generates the AML-1/EVI-1 fusion protein; and the acquisition of t(7;11), which produces the NUP98-HOXA9 fusion protein that causes aberrant self renewal.

• #39

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

  The frequency of additional chromosomal abnormalities is approximately 7% in CML-CP and increases to 40%70% in the advanced phases of disease, as evaluated by standard cytogenetic analysis. […] These aberrations involve acquisition of major alterations, such as the acquisition of additional chromosomes (e.g., +Ph, +8, +19); the acquisition of isochromosome i(17q); the acquisition of t(1;17), which is associated with loss of p53; the acquisition of t(1;21), which affects RUNX1; the acquisition of t(3;21), which generates the AML-1/EVI-1 fusion protein; and the acquisition of t(7;11), which produces the NUP98-HOXA9 fusion protein that causes aberrant self renewal.

• #40 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. […] 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.

• #41 The importance of personalized medicine in chronic myeloid leukemia management: a narrative review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-023-00411-3

  Other mutations such as H396P, E255K, F317L, E255V, M351T, Y253F, H396P, and Y253H have also been detected in the ABL kinase domain that conferred different levels of resistance. […] The overexpression of BCR-ABL1 causes resistance by escalating the oncoprotein concentration, required to be blocked by TKI. […] It is presumed that this overexpression or amplification of BCR-ABL1 leads up to the appearance of point mutations in the kinase domain. […] Among the factors that have contributed to the evolution of CML, causing TKI resistance and disease transfer from CP-CML to more virulent stages through DNA damage, and genomic instability is DNA damage response deregulation (DDR). […] The patient with CML witnesses genomic instability and DNA damage response (DDR) signaling pathway due to reactive oxygen species (ROS) overproduction, which causes replication pressure and centrosomal dysfunction and eventually prevents apoptosis.

• #42 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

  In BP-CML, loss of function of key tumor suppressors may also be mediated by events not acting at the genomic level. […] In CML, the transition from CP to BP is characterized by a progressively increasing impairment of myeloid blast differentiation which determines the stack of myeloid progenitors. […] Epigenetic changes are known to cooperate with genetic events in human tumorigenesis. […] The increased BCR-ABL1 expression observed in BP CML has also been linked to an aberrant regulation of processing, nuclear export and translation of mRNA. […] MicroRNAs (miRNAs) are known to play an essential role in tumorigenesis by post-transcriptional regulation of gene expression. […] Three levels of response to therapy are routinely defined in CML: hematological response, cytogenetic response (reduction in the percentage of BM metaphases positive for the Philadelphia chromosome) and molecular response (reduction in BCR-ABL1 transcript levels, measured in terms of logarithmic reduction from a standardized baseline). […] The mechanisms responsible for resistance are likely to be at least in part different from those underlying disease persistence at the molecular level.

• #43 The non-genomic loss of function of tumor suppressors: an essential role in the pathogenesis of chronic myeloid leukemia chronic phase | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2346-6

  The involvement of miRNAs in CML pathogenesis is highly complex and include both oncogenic miRNA and tumor suppressive miRNAs. In line with the aim of this review, it should be noted that BCR-ABL is able to positively regulate several oncogenic miRNAs which in turn affect the expression of tumor suppressors, with consequent inactivation. […] Morgana/chp-1 can cooperate with BCR-ABL in the pathogenesis of CML and in the development of TKI resistant CML. […] The oncogenic BCR-ABL signal is part of a complex network of interactions that mediate proliferation and survival. Parallel to these signaling transduction pathways, BCR-ABL is also able to mediate the inactivation of several tumor suppressors, through either i) regulation of gene expression, or ii) changes in cellular compartmentalization or iii) directly or indirectly, favoring protein modifications, such as phosphorylation/ubiquitination/acetylation.

• #44 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

  It is thought that intrinsic regulatory systems and extrinsic microenvironmental signals are responsible for controlling quiescence of LSCs. […] In addition, the connection with the bone marrow niche and signaling molecules associated with self-renewal and survival are two key components in the long-term persistence of quiescent LSCs in CML, resulting in resistance to targeted therapy and increased risk of disease recurrence following therapy withdrawal. […] The CML-derived microvesicles (MVs) represent communication vehicles with the microenvironment which can shuttle miRNAs, amphiregulin, as well as BCR-ABL mRNAs to close stromal cells and cause reprogramming of niche cell functions. […] CML-derived exosomes transfer miR-92a and activate SRC signaling, which induces phosphorylation of AKT and ERK1/2 and oncogenic signaling by BCR-ABL.

• #45 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

  However, this activation process can be reduced by TKI treatment. […] In addition, the secretion of exosomes containing amphiregulin along with CML LSCs can promote CML LSCs adhesion and their survival by activation the epidermal growth factor (EGFR) pathway in MSCs and increase secretion of IL-8, which stimulates human vascular endothelial cells to enhance the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). […] Therefore, targeting CXCR2 signaling might be a novel targeted therapy in TKI-resistant CML patients through the suppression of AKT/mTOR and c-MYC. […] The production of fibroblast growth factor 2 (FGF2) by BM-derived MSCs and the decreased level of reactive oxygen species (ROS) in CML LSCs also increases TKI resistance.

• #46 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

  It is thought that intrinsic regulatory systems and extrinsic microenvironmental signals are responsible for controlling quiescence of LSCs. […] In addition, the connection with the bone marrow niche and signaling molecules associated with self-renewal and survival are two key components in the long-term persistence of quiescent LSCs in CML, resulting in resistance to targeted therapy and increased risk of disease recurrence following therapy withdrawal. […] The CML-derived microvesicles (MVs) represent communication vehicles with the microenvironment which can shuttle miRNAs, amphiregulin, as well as BCR-ABL mRNAs to close stromal cells and cause reprogramming of niche cell functions. […] CML-derived exosomes transfer miR-92a and activate SRC signaling, which induces phosphorylation of AKT and ERK1/2 and oncogenic signaling by BCR-ABL.

• #47 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

  It is thought that intrinsic regulatory systems and extrinsic microenvironmental signals are responsible for controlling quiescence of LSCs. […] In addition, the connection with the bone marrow niche and signaling molecules associated with self-renewal and survival are two key components in the long-term persistence of quiescent LSCs in CML, resulting in resistance to targeted therapy and increased risk of disease recurrence following therapy withdrawal. […] The CML-derived microvesicles (MVs) represent communication vehicles with the microenvironment which can shuttle miRNAs, amphiregulin, as well as BCR-ABL mRNAs to close stromal cells and cause reprogramming of niche cell functions. […] CML-derived exosomes transfer miR-92a and activate SRC signaling, which induces phosphorylation of AKT and ERK1/2 and oncogenic signaling by BCR-ABL.

• #48 Chronic myeloid leukemia – Knowledge @ AMBOSS

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

  Result: inhibits physiologic apoptosis and increases mitotic activity uncontrolled proliferation of functional granulocytes. […] 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.

• #49 Chronic Myelogenous Leukemia | CML | MedlinePlus

  https://medlineplus.gov/chronicmyeloidleukemia.html

  The Philadelphia chromosome isn’t passed from parent to child. It happens during your lifetime. The cause is unknown. […] Targeted therapy, which uses drugs or other substances that attack specific cancer cells with less harm to normal cells. For CML, the drugs are tyrosine kinase inhibitors (TKIs). They block tyrosine kinase, which is an enzyme that causes your bone marrow to make too many blasts.

• #50 The importance of personalized medicine in chronic myeloid leukemia management: a narrative review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-023-00411-3

  It is approximated that more than 25% of CML patients will expand resistance to first-line TKI therapy and have to change this, at least once throughout their lifespan. […] Drug resistance mechanisms in patients can be divided into two groups: BCR-ABL-independent mechanisms and BCR-ABL-dependent mechanisms. […] BCR-ABL-dependent mechanisms include mutations of the BCR-ABL kinase domain, mutations outside BCR-ABL kinase domains, compound mutations, amplification or overexpression of BCR-ABL and BCR-ABL-independent mechanisms including activation of alternative pro-survival signaling pathways as a mechanism of resistance, drug influx/efflux activity, clonal evolution, genomic instability, epigenetic modifications, CML stem cells and cytochrome P450 (CYP) isoenzymes polymorphisms. […] The successfulness of therapy with TKI is extremely dependent on suitable BCR-ABL1 drug interplay, and one of the most investigated mechanisms is those related to the reactivation of BCR-ABL1 kinase function.

• #51 An Overview of Myeloid Blast-Phase Chronic Myeloid Leukemia

  https://www.mdpi.com/2072-6694/16/21/3615

  Patients who have BCR-ABL1 kinase domain mutations have a higher likelihood of progression to BC. […] It was reported that the genetic or functional inactivation of p53 seemed the most common abnormality in BC-CML and that the TP53 gene was mutated in 25–30% of patients with MBP-CML. […] The BCR-ABL1 gene may be overexpressed because of genetic, transcriptional, or post-translational mechanisms. […] Although BCR-ABL1-dependent resistance mechanisms are the most common cause of resistance to TKIs, BCR-ABL1-independent mechanisms of resistance occur in about 40% of relapsed patients with CML. […] The bone marrow is composed of hematopoietic and mesenchymal-derived cells. The bone marrow stroma is made up of mesenchyme-derived cells, extracellular matrix, and macrophages. One contributor to drug resistance in CML may be the dysregulated interactions between hematopoietic cells and stromal cells. […] The interactions between these two types of cells are bidirectional and one may be able to influence the other.

• #52 The importance of personalized medicine in chronic myeloid leukemia management: a narrative review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-023-00411-3

  It is approximated that more than 25% of CML patients will expand resistance to first-line TKI therapy and have to change this, at least once throughout their lifespan. […] Drug resistance mechanisms in patients can be divided into two groups: BCR-ABL-independent mechanisms and BCR-ABL-dependent mechanisms. […] BCR-ABL-dependent mechanisms include mutations of the BCR-ABL kinase domain, mutations outside BCR-ABL kinase domains, compound mutations, amplification or overexpression of BCR-ABL and BCR-ABL-independent mechanisms including activation of alternative pro-survival signaling pathways as a mechanism of resistance, drug influx/efflux activity, clonal evolution, genomic instability, epigenetic modifications, CML stem cells and cytochrome P450 (CYP) isoenzymes polymorphisms. […] The successfulness of therapy with TKI is extremely dependent on suitable BCR-ABL1 drug interplay, and one of the most investigated mechanisms is those related to the reactivation of BCR-ABL1 kinase function.

• #53 The importance of personalized medicine in chronic myeloid leukemia management: a narrative review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-023-00411-3

  Point mutations within the ABL kinase domain, as the leading cause of TKI resistance, and other domains that control the conformation of this domain prevent the binding of drugs via changing the BCR-ABL confirmation or by preventing the attaching altogether, leading to acquired resistance instead of primary resistance. […] The mutations manifestation could result from the elective force of preexisting mutant clones, genetic instability derived via BCR-ABL1, and the drug itself, which gently outgrows the drug-sensitive cells. […] T315I (isoleucine replaces threonine in position 315 of BCR-ABL1), as a gatekeeper mutation, was the first mutation shown in recurred CML patients and reasons the highest level of resistance to all kinds of TKIs and the only TKI approved for clinical use in this situation is ponatinib.

• #54 The importance of personalized medicine in chronic myeloid leukemia management: a narrative review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-023-00411-3

  Point mutations within the ABL kinase domain, as the leading cause of TKI resistance, and other domains that control the conformation of this domain prevent the binding of drugs via changing the BCR-ABL confirmation or by preventing the attaching altogether, leading to acquired resistance instead of primary resistance. […] The mutations manifestation could result from the elective force of preexisting mutant clones, genetic instability derived via BCR-ABL1, and the drug itself, which gently outgrows the drug-sensitive cells. […] T315I (isoleucine replaces threonine in position 315 of BCR-ABL1), as a gatekeeper mutation, was the first mutation shown in recurred CML patients and reasons the highest level of resistance to all kinds of TKIs and the only TKI approved for clinical use in this situation is ponatinib.

• #55 The importance of personalized medicine in chronic myeloid leukemia management: a narrative review | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-023-00411-3

  Point mutations within the ABL kinase domain, as the leading cause of TKI resistance, and other domains that control the conformation of this domain prevent the binding of drugs via changing the BCR-ABL confirmation or by preventing the attaching altogether, leading to acquired resistance instead of primary resistance. […] The mutations manifestation could result from the elective force of preexisting mutant clones, genetic instability derived via BCR-ABL1, and the drug itself, which gently outgrows the drug-sensitive cells. […] T315I (isoleucine replaces threonine in position 315 of BCR-ABL1), as a gatekeeper mutation, was the first mutation shown in recurred CML patients and reasons the highest level of resistance to all kinds of TKIs and the only TKI approved for clinical use in this situation is ponatinib.

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