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
Genes involved in the pathogenesis of chronic myelogenous leukemia include BCR and ABL.
Pathogenesis
Genetics
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 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. 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]
Central to the pathogenesis of CML is the fusion of the Abelson murine leukemia (ABL) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22, which results in expression of an oncoprotein, termed BCR-ABL [2]. BCR-ABL is a constitutively active tyrosine kinase that promotes growth and replication through downstream pathways such as RAS, RAF, JUN kinase, MYC, and STAT [3–9]. This influences leukemogenesis by creating a cytokine-independent cell cycle with aberrant apoptotic signals in response to cytokine withdrawal. PMID:24729196
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
Gallery
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![Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell[2]](/images/d/d7/CDR526538-571.jpg)
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell[2]
![Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell[2]](/index.php/File:CDR526538-571.jpg)
References
- ↑ Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet (2007). "Chronic myeloid leukaemia". Lancet. 370 (9584): 342–50. PMID 17662883.
- ↑ National Cancer Institute. Physician Data Query Database 2015.http://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq