Chapter 104. Acute and Chronic Myeloid Leukemia (Part 11) Chronic Myelogenous Leukemia Incidence The incidence of chronic myelogenous leukemia (CML) is 1.5 per 100,000 people per year, and the age-adjusted incidence is higher in men than in women (2.0 versus 1.2). The incidence of CML increases slowly with age until the middle forties, when it starts to rise rapidly. CML incidence for males decreased slightly (4.4%) between 1997 and 2003 as compared to 1977–1997. Definition The diagnosis of CML is established by identifying a clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22. This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22q11 with the ABL (named after the abelson murine leukemia virus) gene located on chromosome 9q34. Untreated, the disease is characterized by the inevitable transition from a chronic phase to an accelerated phase and on to blast crisis in a median time of 4 years. Etiology No clear correlation with exposure to cytotoxic drugs has been found, and no evidence suggests a viral etiology. In the pre-imatinib era, cigarette smoking accelerated the progression to blast crisis and therefore adversely affected survival in CML. Atomic bomb survivors had an increased incidence; the development of a CML cell mass of 10,000/µL took 6.3 years. No increase in CML incidence was found in the survivors of the Chernobyl accident, suggesting that only large doses of radiation can induce CML. Pathophysiology The product of the fusion gene resulting from the t(9;22) plays a central role in the development of CML. This chimeric gene is transcribed into a hybrid BCR/ABL mRNA in which exon 1 of ABL is replaced by variable numbers of 5' BCR exons. Bcr/Abl fusion proteins, p210 BCR/ABL , are produced that contain NH 2 - terminal domains of Bcr and the COOH-terminal domains of Abl. A rare breakpoint, occurring within the 3' region of the BCR gene, yields a fusion protein of 230 kDa, p230 BCR/ABL . Bcr/Abl fusion proteins can transform hematopoietic progenitor cells in vitro. Furthermore, reconstituting lethally irradiated mice with bone marrow cells infected with retrovirus carrying the gene encoding the p210 BCR/ABL leads to the development of a myeloproliferative syndrome resembling CML in 50% of the mice. Specific antisense oligomers to the BCR/ABL junction inhibit the growth of t(9;22)-positive leukemic cells without affecting normal colony formation. The mechanism(s) by which p210 BCR/ABL promotes the transition from the benign state to the fully malignant one is still unclear. Messenger RNA for BCR/ABL can occasionally be detected in normal individuals. However, attachment of the BCR sequences to ABL results in three critical functional changes: (1) the Abl protein becomes constitutively active as a tyrosine kinase (TK) enzyme, activating downstream kinases that prevent apoptosis; (2) the DNA- protein-binding activity of Abl is attenuated; and (3) the binding of Abl to cytoskeletal actin microfilaments is enhanced. Disease Progression The events associated with transition to the acute phase, a common occurrence in the pre-imatinib era, were extensively studied. Chromosomal instability of the malignant clone, resulting, for example, in the acquisition of an additional t(9;22), trisomy 8, or 17p- (p53 loss), is a basic feature of CML. Acquisition of these additional genetic and/or molecular abnormalities is critical to the phenotypic transformation. Large deletions adjacent to the translocation breakpoint on the derivative 9 chromosome, detected by microsatellite polymerase chain reaction (PCR) or FISH, are associated with shorter survival times. Heterogeneous structural alterations of the p53 gene, as well as structural alterations and lack of protein production of the retinoblastoma gene and the catalytic component of telomerase, have been associated with disease progression in a subset of patients. Rare patients show alterations in the rat sarcoma viral oncogene homolog (RAS). Sporadic reports also document the presence of an altered MYC (named after the myelocytomatosis virus) gene. Progressive de novo DNA methylation at the BCR/ABL locus and hypomethylation of the LINE-1 retrotransposon promoter herald blastic transformation. Further, interleukin 1β may be involved in the progression of CML to the blastic phase. In addition, functional inactivation of the tumor suppressor protein phosphatase A2 may be required for blastic transformation. Finally, CML that develops resistance to imatinib is at an increased risk of progressing to accelerated/blast crisis. Multiple pathways to disease transformation exist, but the exact timing and relevance of each remain unclear. . Chapter 104. Acute and Chronic Myeloid Leukemia (Part 11) Chronic Myelogenous Leukemia Incidence The incidence of chronic myelogenous leukemia (CML) is 1.5 per. transition from a chronic phase to an accelerated phase and on to blast crisis in a median time of 4 years. Etiology No clear correlation with exposure to cytotoxic drugs has been found, and no evidence. chromosomes 9 and 22. This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22q11 with the ABL (named after the abelson murine leukemia