Variant translocation in CML – Is it really the same as the typical translocation?
Purpose: To assess the prognostic significance of variant translocations in chronic myeloid leukemia (CML).
Background: CML is genetically characterized by the presence of t(9;22) that results in a BCR/ABL fusion gene on the derivative chromosome 22 termed the Ph chromosome. In 5-10% of the cases, this fusion gene is generated by variant translocations, involving 9q, 22q, and at least one additional genomic locus. Studies on the prognostic significance of these variant Ph translocations revealed conflicting results. In addition, deletions in the derivative chromosome 9 [der(9)], which is associated with an adverse outcome, are reportedly more frequent among variant translocation cases.
Methods: Cytogenetic and FISH data from CML patients with variant translocations tested at our laboratory were collected from 1990 to 2005 and analyzed. Correlation with available clinical information was carried out. The results were compared with published data on typical translocations of CML.
Results: A total of 22 patients were identified with variant translocations of CML. Eight (36.4%) were in accelerated phase/blast crisis, comparable to that reported for CML with a typical translocation. Survival information was available in only six patients, and four (66.7%) were deceased. By FISH analysis, deletion of der(9) was observed in seven patients (31.8%), which is higher than that reported for typical translocation cases (18%). Sequential changes of 9q deletions were also common based on interphase FISH. Distinct signal patterns suggesting different mechanisms in the genesis of variant translocations frequently co-exist in a single case. All Gleevec-treated patients had better survival than patients receiving other therapies.
Conclusions: Our data challenge the notion that deletions of 9q occur at the same time as the formation of Ph chromosome and suggest that 9q deletion could also be acquired as the disease progresses. Variant translocations may be formed by a mixture of 1-step and 2-step mechanisms. Proper assessment of the prognostic significance of variant translocations requires better categorization of these translocations based on their mechanisms of genesis and 9q deletion status.