Chapter 104. Acute and Chronic Myeloid Leukemia (Part 11)

Chronic Myelogenous LeukemiaIncidence 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.DefinitionThe diagnosis of CML is established by identifying a clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation betweenchromosomes 9 and 22. This translocation results in the head-to-tail fusion of the breakpoint cluster region...
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Chapter 104. Acute and Chronic Myeloid Leukemia (Part 11) Chapter 104. Acute and Chronic Myeloid Leukemia (Part 11) Chronic Myelogenous Leukemia Incidence The incidence of chronic myelogenous leukemia (CML) is 1.5 per 100,000people 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 middleforties, 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 ahematopoietic stem cell possessing a reciprocal translocation betweenchromosomes 9 and 22. This translocation results in the head-to-tail fusion of thebreakpoint cluster region (BCR) gene on chromosome 22q11 with the ABL (namedafter the abelson murine leukemia virus) gene located on chromosome 9q34.Untreated, the disease is characterized by the inevitable transition from a chronicphase 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, andno evidence suggests a viral etiology. In the pre-imatinib era, cigarette smokingaccelerated the progression to blast crisis and therefore adversely affected survivalin CML. Atomic bomb survivors had an increased incidence; the development of aCML cell mass of 10,000/µL took 6.3 years. No increase in CML incidence wasfound in the survivors of the Chernobyl accident, suggesting that only large dosesof radiation can induce CML. Pathophysiology The product of the fusion gene resulting from the t(9;22) plays a centralrole in the development of CML. This chimeric gene is transcribed into a hybridBCR/ABL mRNA in which exon 1 of ABL is replaced by variable numbers of 5BCR exons. Bcr/Abl fusion proteins, p210BCR/ABL, are produced that contain NH2-terminal domains of Bcr and the COOH-terminal domains of Abl. A rarebreakpoint, occurring within the 3 region of the BCR gene, yields a fusion proteinof 230 kDa, p230BCR/ABL. Bcr/Abl fusion proteins can transform hematopoieticprogenitor cells in vitro. Furthermore, reconstituting lethally irradiated mice withbone marrow cells infected with retrovirus carrying the gene encoding thep210BCR/ABL leads to the development of a myeloproliferative syndrome resemblingCML in 50% of the mice. Specific antisense oligomers to the BCR/ABL junctioninhibit the growth of t(9;22)-positive leukemic cells without affecting normalcolony formation. The mechanism(s) by which p210 BCR/ABL promotes the transition from thebenign state to the fully malignant one is still unclear. Messenger RNA forBCR/ABL can occasionally be detected in normal individuals. However,attachment of the BCR sequences to ABL results in three critical functionalchanges: (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 tocytoskeletal actin microfilaments is enhanced. Disease Progression The events associated with transition to the acute phase, a commonoccurrence in the pre-imatinib era, were extensively studied. Chromosomalinstability of the malignant clone, resulting, for example, in the acquisition of anadditional 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 tothe phenotypic transformation. Large deletions adjacent to the translocationbreakpoint on the derivative 9 chromosome, detected by microsatellite polymerasechain reaction (PCR) or FISH, are associated with shorter survival times.Heterogeneous structural alterations of the p53 gene, as well as structuralalterations and lack of protein production of the retinoblastoma gene and thecatalytic component of telomerase, have been associated with disease progressionin a subset of patients. Rare patients show alterations in the rat sarcoma viraloncogene homolog (RAS). Sporadic reports also document the presence of analtered MYC (named after the myelocytomatosis virus) gene. Progressive de novoDNA methylation at the BCR/ABL locus and hypomethylation of the LINE-1retrotransposon promoter herald blastic transformation. Further, interleukin 1βmay be involved in the progression of CML to the blastic phase. In addition,functional inactivation of the tumor suppressor protein phosphatase A2 may berequired for blastic transformation. Finally, CML that develops resistance toimatinib is at an increased risk of progressing to accelerated/blast crisis. Multiplepa ...