CHRONIC MYELOID LEUKEMIA
Chronic myeloid leukemia results from the malignant transformation of a pluripotent bone marrow stem cell. Typically, the disease has a triphasic course with an initial chronic phase (median duration 3.5 years) followed by an accelerated phase and then, after 3–12 months, an acute blastic phase associated with a poor response to therapy. The hallmark of chronic myeloid leukemia is the Philadelphia chromosome (Ph), which was the first consistent chromosomal aberration to be associated with human malignancy (Nowell and Hungerford 1960). It is now recognized that the Ph chromosome is present in more than 90 % of patients with chronic myeloid leukemia and that a proportion of apparently Ph-negative chronic myeloid leukemia have a variant Ph translocation not visible by cytogenetic techniques (Kurzrock et al. 1988). The Ph chromosome is not specific for chronic myeloid leukemia, and it is also found (and is associated with a poor prognosis) in a small proportion of patients with ALL (20 % of adults, 5 % children) and AML (2 % of adults). The classic Ph3 chromosome results from a translocation involving chromosomes 9 and 22, (t(9; 22)(q34; q11)). The breakpoint on chromosome 9 involves the Abelson oncogene (ABL), and on chromosome 22, the breakpoints occur within a small region that was originally designated the breakpoint cluster region (BCR). The BCR is a central segment within a 90- kb gene, now named the BCR gene (Laurent et al. 2001). The 9;22 translocation results in the juxtaposition of proximal 5′ BCR gene exons (1, 2, and 3) and ABL sequences (exons 2–11, exons 1a and 1b).
Environmental agents associated with chronic myeloid leukemia include irradiation and chemical (e.g., benzene) exposure (Jacobs 1989), but there is relatively little evidence for a genetic predisposition. Familial chronic myeloid leukemia has been reported, and abnormal hematological investigations (evidence of a myeloproliferative disorder) have been observed in the healthy close relatives of cases. Nevertheless, familial cases of chronic myeloid leukemia appear to be rare.