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BCR-ABL tyrosine kinase

ABL gene

ABL gene is a proto-oncogene located on the long arm of the ninth chromosome. It encodes cytoplasmic and nuclear tyrosine kinase, which takes part in processes involving cell differentiation, cell division, cell adhesion and stress response. Activity of ABL1 in these processes is negatively regulated by its SH3 domain. When deleted, ABL1 turns into oncogene. This occurs when ABL is fused with BCR gene, creating active BCR-ABL tyrosine kinase.

C-abl Kinase domain with the activator(cmpd6), 2-cyano-N-(4-(3,4- dichlorophenyl)thiazol-2-yl)acetamide

Drag the structure with the mouse to rotate

BCR gene

BCR (breakpoint cluster region) gene is located on the long arm of chromosome 22. The function of sole BCR protein is yet not completely understood. Studies suggest that it may act as a GTPase activating protein and also as a kinase involved in regulating signalling within cells.

Structure of bcr-homology domain,

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BCR-ABL gene

BCR-ABL gene is a result of reciprocal somatic translocation of genetic material between the long arms of chromosome 9 and 22. This fusion oncogene encodes a hybrid protein - BCR-ABL tyrosine kinase, containing domains from both the BCR and the ABL1 gene. BCR-ABL acts as an activator of myeloid proliferation causing chronic myeloid leukemia (CML). This gene is found in 95% of cases of CML, occasionally found also in different kinds of leukemia such as the acute lymphatic leukemia (5% children patients and 25% of adult patients) or the acute myeloid leukemia (2% of cases). The breaking point of ABL gene is usually before the second exon - a2 exon, location of BCR breakpoint varies. Depending on the exact location of gene fusion, there are three clinically important variants of BCR-ABL: 1) BCR translocation breakpoint located in “major” area (M-bcr) The second exon of ABL is fused to exon b2 or b3 of BCR. Product of such fusion has molecular weight of 210 kD. This fusion gene is identified as p210 and is typical for CML. 2) BCR translocation breakpoint found in intron area “minor” (m-bcr) In this case of fusion, the first exon (e1) of BCR becomes the part of BCR-ABL gene. Such a gene is denoted as e1a2 and its coding product is called p190 (molecular weight 190 kD). p190 is common in acute lymphatic leukemia and rarely occurs in chronic myeloid leukemia. 3) BCR translocation breakpoint situated in “micro” area Here, fusion of the 19. exon of BCR gene and the second exon of ABL gene forms e19a2 gene. The resulting protein is called p230.


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Due to the non-presence of ABL’s SH3 domain and site for myristate binding site, Bcr-Abl is “always on.


Philadelphia chromosome

Named after the city where it was first discovered and described, Philadelphia chromosome (Ph) is a specific genetic abnormality in chromosome 22, a result of a reciprocal translocation t(9;22)(q34;q11) of long arms of chromosomes 9 and 22. It is one of the most common cytogenetic abbreviations in hematologic diseases. The creation of Ph occurs during the life of a patient. The presence of Philadelphia chromosome is possible to be tested with molecular cytogenetic examinations such as multicolour FISH (M-FISH), spectral karyotypization (SKY) or multicolour banding (M-BAND).

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Positively detected Philadelphia chromose using FISH - Fluorescence in situ hybridization.


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Reciprocal somatic translocation of genetic material between the long arms of chromosome 9 and 22 results in the Philadelphia chromosome.


BCR-ABL tyrosine kinase

BCR-ABL is an active cytoplasmic tyrosine kinase, which disrupts signalling paths. It is an always active kinase that constantly forces cells to uncontrollably proliferate, therefore causing leukemic cell phenotype. When not fused with BCR, ABL’s involvement in cell division is controlled by a complex set of intramolecular interactions like SH3, SH2 subdomains and myristoylated (Myr) N-cap region. Present myristoylated cap results in a conformational change (binding to C-lobe of the kinase induces a 90 ° bending of the C-terminal α-I helix of the kinase domain, producing a complete docking site for the SH2 domain enabling the assembly of the autoinhibited conformation) in kinase domain making it inactive. In BCR-ABL, Myr is not present – substituted by BCR. Similar to other tyrosine kinases, BCR-ABL transfers phosphate from ATP to tyrosine residue on a substrate. Kinases become activated (activity on the catalytic site), when bound to ATP on the ATP binding site. Both the ATP binding site and the catalytic site of BCR-ABL are found on the ABL domain of the protein. BCR-ABL activates RAS, Jak/Stat, PI-3 kinase pathways resulting in increased proliferation and differentiation. Furthermore, activation of the RAS, Jun-kinase and PI-3 pathways inhibit apoptosis. Activation of the mentioned pathways occurs via a series of adapter proteins. Many more pathways have been found to be affected.

Chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a clonal tumor disease resulting from the neoplastic transformation of a hematopoietic stem cell. It accounts for 15% of all leukemias. The disease incidence is 1,6 new cases per 100 000 people every year. The average age at onset of CML is 64 years. The disorder is characterized by the heterogeneity of its course andby the presence of a chromosomal abnormality called the Philadelphia Chromosome found in 95% of all cases. It was first described by Peter Nowell and David Hungerford in Philadelphia in 1960. The course of CML is divided into three phases. The first phase is called the chronic phase. Patients in this phase are either asymptomatic or experience mild symptoms such as fatigue, abdominal fullness, easy bruising or bleeding. 85% of sufferers are diagnosed in this phase with median survival at 5 to 6 years. Typical reflection of this phase is leukocytosis in the complete blood count and the representation of all developmental stages of leukocytes, some of which may be myeloblasts. Bone marrow aspiration is also characteristic as splenomegaly dominates the objective finding. The diagnosis is confirmed by the detection of Ph-chromosome or of the BCR-ABL fusion gene. The tumorous cells become more aggressive as the patient enters the accelerated phase. That is when the disease control becomes more difficult. The proliferation speed increases rapidly as well as the cells’ resistance to treatment. The final phase of the disease is called the blast crisis. With its rapid progression and short survival, the blast crisis is usually fatal. The median survival is 3 to 6 months and it behaves like an acute leukemia. The qualitative determination of BCR-ABL fusion transcript by reverse transcriptase polymerase chain reaction (RT-PCR) allows identifying patients in which leukemic cells persist or reappear after bone marrow transplantation for its sensitivity exceeds the sensitivity of commonly used cytogenetic methods (which detect the presence of Ph chromosome). However, to determine whether the number of leukemic cells increases, quantitative RT-PCR needs to be used. Patients in both cytogenetic and hematological remission allow early detection of this fusion gene – molecular relapse – which leads to early treatment that is less intensive for the patients, less expensive and much more effective. Treatment begins immediately after the diagnosis, which usually happens in the chronic phase of CML. Although there are many types of therapy, such as myelosuppressive therapy, leukopheresis therapy, splenectomy or interferon alfa-2b treatment, the most common are Bcr-Abl tyrosine-kinase inhibitors, drugs that specifically target BCR-ABL. The first of this new class of drugs was Imatinib Mesylate. Its occupation of the tyrosine-kinase active site leads to a decrease in Bcr-Abl activity. Other tyrosine kinase inhibitors were developed over time to overcome imanitib resistance – Dasatinib, Nilotinib, Radotinib, Bosutinib. However, in some cases, CML cells develop a change in the BCR-ABL oncogene known as a T315I mutation, which causes their resistancy to most of the tyrosine kinase inhibitors developed so far. More drugs aimed at this mutation are now being tested.

Bcr-Abl tyrosine-kinase inhibitor

Imatnib is a tyrosin kinase inhibitor - competetively binds to the kinase domain of Bcr-Abl. Substrate cannot be bound - the activity of Bcr-Abl is inhibited.

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Structure of imatnib - medication used to treat chronic myeloid leukemia.

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Proteopedia Page Contributors and Editors (what is this?)

Barbora Schramlová

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