CML: Linked to a Single Molecular Abnormality

• The Philadelphia (Ph) chromosome, which is present in 95% of patients with CML, produces an abnormal, constitutively activated Bcr-Abl tyrosine kinase that is linked to malignant transformation.1,2

• The Ph chromosome, a shortened chromosome 22, is formed by a reciprocal translocation,

t(9;22)(q34;q11), between chromosomes 9 and 22. A segment of the abl gene (Abelson mouse leukemia proto-oncogene) on chromosome 9 coding for a nonreceptor tyrosine kinase is fused to the bcr gene (breakpoint cluster region) on chromosome 22 to form an abnormal hybrid bcr-abl gene.3

• The bcr-abl gene is transcribed into a hybrid messenger RNA; the translation product of this RNA is an abnormal fusion protein with tyrosine kinase activity.

• The abnormal Bcr-Abl kinase identified in CML is an attractive target for rational drug design.

• The Ph chromosome is present in all myeloid cell lineages and evidence indicates that malignant transformation to CML originates at the stem cell level.3,4

• The Ph chromosome and bcr-abl are detected using several techniques of differing sensitivity:

– Standard cytogenetic analysis (karyotyping) of interphase bone marrow cells detects the Ph

chromosome with a sensitivity of ~1/20–25.

– Fluorescence in situ hybridization (FISH) detects the bcr-abl fusion gene in peripheral blood or bone marrow specimens with a sensitivity of ~1/250.

– Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) quantifies the level of bcr-abl  expression in peripheral blood or bone marrow with a sensitivity of ~1/105 to 1/106.

References

1. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the p210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830.

2. Heisterkamp N, Jenster G, ten Hoeve J, et al. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251-253.

3. Pasternak G, Hochhaus A, Schultheis B, et al. Chronic myelogenous leukemia: molecular and cellular aspects. J Cancer Res Clin Oncol. 1998;124:643-660.