Cytogenetic Changes
BCR-ABL-Positive Patients
At least 95% of patients with chronic myelogenous leukemia have an acquired distinctive cytogenetic abnormality of chromosome 22, known as the Philadelphia (Ph) chromosome. The shortened Ph chromosome is the result of a reciprocal translocation of chromosomes 9 and 22, a process that produces the BCR-ABL fusion gene.
The normal BCR gene is located on chromosome 22qll.21. The gene encodes a phosphoprotein associated with serine/threonine kinase activity and shows autophosphorylation activity as well as transphosphorylation activity for several protein substrates. The c-ABL gene, mapping on chromosome 9q34, codes for a tyrosine kinase with nuclear localization. The DNA-binding activity of the ABL protein is regulated by CDC2-mediated phosphorylation, suggesting a cell-cycle function for ABL. The gene is also implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. The tyrosine kinase activity of nuclear ABL is regulated in the cell cycle through a specific interaction with the Rb protein. ABL activity is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL into an oncogene. The translocation t(9;22)(q34;ql 1), which transposes the ABL gene from chromosome 9 to the center of the BCR gene on chromosome 22, results in a head-to-tail fusion of these two genes and the formation of the Ph chromosome. Although the position of the breakpoint, or rearrangement, on chromosome 9 varies considerably, the breakpoint on chromosome 22 is clustered in an area called the breakpoint cluster region. Investigators have demonstrated a correlation between the site of the breakpoint within the breakpoint cluster region on chromosome 22 and the length of time between presentation and onset of accelerated-phase chronic myelogenous leukemia. Researchers have discovered that patients with a 5′ breakpoint have a fourfold longer chronic phase than do those with a 3′ breakpoint.
The BCR-ABL fusion gene (also known as the BCR-ABL rearrangement) expresses an enzyme, the BCR-ABL oncoprotein, which has abnormally high tyrosine kinase activity compared with normal cells. This enzyme phosphorylates a number of substrates, activating a series of signal transduction pathways and, in turn, alters stem-cell function. The result is the chronic phase of chronic myelogenous leukemia.
The remaining 5% or less of patients with chronic myelogenous leukemia do not have a shortened chromosome 22 but possess the BCR-ABL rearrangement (Ph-negative, BCR-ABL-positive), which can be detected by sensitive molecular techniques such as reverse transcription polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization.
A few patients do not exhibit the BCR-ABL rearrangement but, because they have clinical and morphological features suggestive of chronic myelogenous leukemia, are still given a diagnosis of chronic myelogenous leukemia (discussed further on).
Although the BCR-ABL rearrangement is the hallmark of chronic myelogenous leukemia, it is not unique to the condition and is present in up to 10% of patients with acute lymphocytic leukemia and acute myelogenous leukemia who have no evidence of antecedent chronic myelogenous leukemia. Accordingly, the diagnosis of chronic myelogenous leukemia is not based simply on the presence of the chromosome abnormality but requires the presence of typical clinical and morphological features.
The presence of the BCR-ABL rearrangement is used to monitor the response of a patient to therapy; patients who have a complete cytogenetic response (i.e., no detectable BCR-ABL expression) following therapy have a good prognosis.
Clonal Evolution
Scientists hypothesize that genetic changes secondary to the BCR-ABL rearrangement drive the transition from the chronic phase to the accelerated and blastic phases. Indeed, the frequency of additional cytogenetic changes (clonal evolution [CE]) increases with advancing stage, rising from 30% in the accelerated phase up to 80% in the blastic phase. Given that chronic-phase chronic myelogenous leukemia is a manageable condition carrying no mortality, whereas transformation heralds certain death, understanding the process behind transformation is a key area of genetic research. The genetic abnormalities that have been identified to date are diverse, and it remains unclear whether common blockable pathways exist.
On average, a patient in blastic crisis carries three cytogenetic abnormalities out of a wide range reported so far. Chromosomes 8, 17, 19, and 22 are most often involved in CE. This involvement is almost entirely the result of the frequent occurrence of trisomy 8 (trisomy means having three copies of a given chromosome in each somatic cell rather than the normal number of two), trisomy 19, an extra Ph chromosome, and isochromosome 17, which is closely associated with the myeloid type of blast crisis. At least one of these four major cytogenetic changes is found in 71% of Ph-positive cases of chronic myelogenous leukemia. Minor cytogenetic changes have also been documented: trisomies of chromosomes 17 and 21; monosomies of 7, 17 and Y; and translocation t(3;21) (q26;q22). At least one of these cytogenetic changes can be detected in 15% of all Ph-positive chronic myelogenous leukemia patients.
BCR-ABL-Negative Patients
As previously mentioned, approximately 5% of patients with clinical and morphological features consistent with chronic myelogenous leukemia have no evidence of the BCR-ABL rearrangement. These patients are generally older and often have thrombocytopenia, lower blood cell counts, greater monocytosis, lower bone marrow myeloid: erythroid ratios, and less basophilia than BCR-ABL-positive patients do. In fact, patients in this group do not have chronic myelogenous leukemia, even though they may be given this diagnosis, but rather have one of a variety of hematologic disorders, such as chronic myelomonocytic leukemia.
Although these patients have a low risk of blastic transformation, their median survival is shorter than that of BCR-ABL-positive chronic myelogenous leukemia patients. The natural history of BCR-ABL-negative patients is characterized by progressive leukemic burden, extramedullary leukemic infiltrates, poor response to chemotherapy, and bone marrow failure. Because of the low incidence of BCR-ABL-negative disease, it does not warrant further discussion.
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