Current Status of Treatment for Chronic Myelogenous Leukemia

Kathryn S. Kolibaba, MD, Brian J. Druker, MD

In This Article

The Philadelphia Chromosome and CML

In 95% of CML cases, the product of a reciprocal translocation between chromosomes 9 and 22, the Philadelphia chromosome, is detectable [15] (Figure 1). This balanced translocation juxtaposes sequences of the breakpoint cluster region (BCR) on chromosome 22 with the c-ABL tyrosine kinase gene on the long arm of chromosome 9 [16] (Figure 2). The BCR-ABL fusion gene in CML produces a 210 kD protein in which the first exon of c-ABL has been replaced by BCR sequences encoding either 927 or 902 amino acids.[17]

Figure 1.

The Philadelphia chromosome.

Figure 2.

Molecular defects due to rearrangement of the Philadelphia chromosome.

The Philadelphia chromosome is found by cytogenetic analysis in 90% of patients with CML. In half of Philadelphia chromosome-negative patients, evidence of the BCR-ABL rearrangement can be detected by PCR, Southern blot, reverse-transcriptase (RT)-PCR, fluorescence in situ hybridization (FISH), or Western blot analysis.[18,19,20] These Philadelphia chromosome-negative (Ph-negative), BCR-ABL-positive patients have a similar clinical presentation, response to therapy, and prognosis as Philadelphia chromosome-positive (Ph-positive) CML patients.[20,21]

However, neither the Philadelphia chromosome nor BCR-ABL is pathognomonic of CML, as they are present in other human hematologic malignancies. p210 BCR-ABL is found in 95% of patients with CML, but is detected in approximately 5%-10% of adults with acute myelogenous or acute lymphoblastic leukemia for whom there is no evidence of antecedent CML. Another BCR-ABL fusion protein of 185 kD, containing BCR sequences from exon 1 (426 amino acids) fused to exons 2-11 of c-ABL, occurs in 10% of adult cases and 5%-10% of pediatric cases of acute lymphoblastic leukemia, but not in CML.[22] Thus, the presence of the Philadelphia chromosome alone is not sufficient for the diagnosis of CML, which also requires the presence of typical clinical features of the disease. Various BCR-ABL fusion proteins are shown in Figure 2.

The BCR-ABL fusion creates a chimeric gene whose protein product has tyrosine kinase activity elevated several-fold over the normal c-ABL gene product.[23] The tyrosine kinase activity of the BCR-ABL protein is required for transformation,[24,25] and the BCR-ABL fusion gene causes a syndrome resembling CML in syngeneic mice.[26] Thus, BCR-ABL has been implicated as the cause of CML.


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