Understanding CML
Pathophysiology
Chronic myeloid leukaemia was the first cancer demonstrated to have a genetic abnormality as the underlying cause of disease. In 1960, CML was observed to be associated with an abnormal chromosome, termed the “Philadelphia” chromosome for the city where it was discovered.1,2 The Ph chromosome is the result of a translocation, or exchange of genetic material, between the long arms of chromosomes 9 and 22 (Figure 1).3 The Ph chromosome is present in 95% of patients with CML, making it nearly pathognomonic of this disease. In addition, it is present in cells of all lineages in CML, suggesting that malignant transformation originates at the stem-cell level.5,4 The Ph chromosome also is seen in other forms of leukaemia. Approximately 5% of childhood ALL, 15%-30% of adult ALL, and nearly 2% of AML cases are Ph+.6,4
Figure 1. BCR-ABL oncogene.
Click on the image to enlarge
The chromosomal translocation that generates the Ph chromosome ligates the breakpoint cluster region (BCR) gene of chromosome 22 to be in continuity with the gene encoding the ABL tyrosine kinase on chromosome 9.7,8 The splicing of these 2 genetic segments results in an abnormal hybrid BCR-ABL gene that encodes a continuously activated BCR-ABL fusion protein. This gene product stimulates a mitogenic signal cascade that enables the massive expansion of the granulocytic cell lineage, which characterises the chronic phase of this disease.10 Depending on the specific location of the translocation crossover splice point, fusion gene products of varying sizes may be produced, which are denoted by their molecular weight in kilodaltons. The p210BCR-ABL fusion protein is expressed primarily in CML; the p185BCR-ABL form is associated with approximately 20%-30% of cases of Ph+ ALL; and p230BCR-ABL is observed only in a subset of patients with chronic neutrophilic leukaemia.10
The Ph chromosome can be detected by standard cytogenetic techniques in most patients.8,11 In patients who are cytogenetically negative for the Ph chromosome, molecular techniques such as fluorescence in situ hybridisation (FISH) or reverse transcription polymerase chain reaction (RT-PCR) may be useful in detecting BCR-ABL.8 In addition, the use of these special techniques may have implications in disease staging or assessing residual disease.5
Additional cytogenetic and molecular alterations are often found in patients with CML during the progression from chronic to blast-crisis phase. It is unclear whether the transformation of CML from chronic to blast-crisis phase involves cooperation between BCR-ABL and these additional abnormal genes. Current research is investigating potential cooperation between BCR-ABL and secondary genetic defects, as well as the role of these secondary fusion-gene products in leukaemogenesis.9
BCR-ABL Signalling
Normal ABL tyrosine-kinase activity in WBCs is associated with the regulation of cellular proliferation and differentiation. BCR-ABL has constitutive tyrosine kinase activity and participates in intracellular signal transduction pathways that promote cell proliferation and suppress apoptosis (Figure 2).7,8Key pathways implicated thus far in transduction of oncogenic signals include those involving RAS, MYC, and mitogen-activated protein kinases, as well as activators of transcription and phosphatidylinositol 3-kinase8 In addition, BCR-ABL can affect adaptor proteins (eg, GAB2) and phosphatases (eg, SHIP1), which have a role in fine-tuning these pathways.12 Constitutive activity of BCR-ABL imparts a growth advantage to leukaemic cells by usurping the physiologic functions of the normal ABL enzyme.5,7,8 This influence is exerted through 3 mechanisms: increased signal transduction of proliferation pathways and increased cytokine-independent growth; inhibition of pathways that normally result in apoptosis; and alteration of adhesion pathways as well as other cytoskeletal abnormalities that results in the failure of CML cells to organise, adhere, and transfer signals within bone marrow.8
Increased understanding of the pathways involved in leukaemogenic signal transduction may reveal additional targets for therapy.
Figure 2. BCR-ABL tyrosine kinase and intracellular signal transduction.
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References:
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