Ph-Negative Chronic Myeloid Leukemia: The Nature of the Breakpoint Junctions and Mechanism of ABL Transposition

CML is a well-defined hematological and clinical entity which sooner or later progresses to blast crisis and death of the patient. Leukemic cells of about 95% of patients show the Ph chromosome which is evidence of the t(9;22)(q34;q11), the cytogenetic rearrangement whereby the BCR gene on chromosome 22 and the ABL gene on chromosome 9 are joined together. The juxtaposition of these genes deregulates the usual function of ABL and causes leukemia. Leukemic cells of the remaining 5% (approximate) of CML patients show complex translocations or have a normal karyotype. Complex translocations achieve the same juxtaposition of BCR and ABL as the standard t(9;22). The Ph chromosome is usually present but may be masked. The final result of a complex translocation can be an apparently normal karyotype and, although BCR and ABL are juxtaposed, there is no Ph chromosome. This is the origin of some cases of Ph-negative CML, in others, part of chromosome 9 including ABL is inserted within the BCR gene. We believe that simple and complex recombinations and insertions are each caused by a single concerted event which breaks a number of adjacent DNA strands at the same time, followed by their mismatched joining and consequent recombination.

The association of BCR-ABL is the essential etiological feature of CML and can be explained, in all cases investigated, by chromosomal rearrangement which takes the form of simple or complex translocations or chromosome insertion. Events that initiate chromosome rearrangement are therefore important in the etiology of CML. Chromosome rearrangement is the result of abnormal DNA recombination which may be caused by an error in normal recombination processes or by endogenous and exogenous mutagens such as chemicals or radiation. These can be regarded as the prime causes of CML.