Chronic myelogenous leukemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]
Overview
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent bone marrow stem cells. The hallmark of CML is the formation of the Philadelphia chromosome resulting from the reciprocal t(9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q-. results in a BCR-ABL fusion gene and production of a BCR-ABL fusion protein. The gene product of the BCR-ABL gene constitutively activates numerous downstream targets including c-myc, Akt and Jun, all of which cause uncontrolled proliferation and survival of CML cells.
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Pathogenesis
Genetics
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the occurrence of the Philadelphia chromosome which is thought to be a definitive diagnostic marker for CML. In Philadelphia chromosome translocation, parts of two chromosomes (the 9th and 22nd by conventional karyotypic numbering) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL ("abelson murine leukemia") gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). 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 that promotes growth and replication through downstream pathways such as RAS, RAF, JUN kinase, MYC, and STAT. In turn BCR-ABL activates a cascade of proteins which 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.[1]. PMID:24729196/26434969/26625737
Chronic myeloid leukemia (CML), a malignant haematopoeitic stem cell disease, characterized by the occurrence of the Philadelphia chromosome which is thought to be a definitive diagnostic marker for CML and is present in almost 90% of the patients (Hagop et al., 2002). This chromosome results due to the balanced reciprocal translocation t (9; 22) (q34; q11). The fusion of the Abelson murine leukemia (ABL) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22 gives rise to the BCR-ABL oncogene that encodes an oncoprotein (Saad et al., 2009). The breakpoints in the BCR gene has been shown to be clustered in three regions, (a) a 5.8 kb region spanning exons 12-16 (e12-e16), called the major breakpoint cluster region (M-bcr) that codes a 210 kDa chimeric protein (p210), (b) a 55 kb sequence of the first intron (e1-e2) called the minor breakpoint cluster region (m-bcr) that encodes a 190 kDa chimeric protein (p190) and finally intron 19, called μ-bcr forming a resultant fusion transcript of 230 kDa protein (p230) (Fausel, 2007; Yuan et al., 2014). Studies show an association between the genetic modifications within the precursor haematopoietic stem cells that may lead to the development of chronic myeloid leukemia (Meggyesi et al., 2011; Gulzar et al., 2012).PMID:26625737
CML is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent bone marrow stem cells.9 The hallmark of the disease is the presence of a reciprocal t(9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q-. The latter, known as the Philadelphia (Ph) chromosome, results in a BCR-ABL fusion gene and production of a BCR-ABL fusion protein;7 BCR-ABL has constitutive tyrosine kinase activity10 and is necessary and sufficient for production of the disease.6 In a minority of cases, (5–10%), the Ph chromosome is cytogenetically cryptic, often due to a complex translocation, and the diagnosis requires fluorescent in situ hybridization (FISH) to demonstrate the BCR-ABL fusion gene or polymerase chain reaction (PCR) to demonstrate the BCR-ABL mRNA transcript.11 A 210 kilodalton BCR-ABL transcript (p210) transcribed from the most common rearrangements between exons 13 or 14 of BCR and exon 2 of ABL (known as e13a2 (or b2a2) and e14a2 (or b3a2), respectively) is most common, but rare cases will have alternative BCR-ABL breakpoints, leading to a p190 transcript [from the e1a2 rearrangement, most typically seen in Ph-positive acute lymphoblastic leukemia (ALL)], or p230 transcript.11 Demonstration of the typical hematopathologic features and either the t(9;22)(q34;q11.2), by conventional cytogenetics or FISH and/or BCR-ABL by PCR is required for diagnosis.PMID:26434969