Letter to the editor

A masked BCR/ABL rearrangement in a case of chronic myeloid leukemia with translocation t(3;9)(p14;q34)

Chronic myeloid leukemia (CML) is the prototype cytogenetic malignancy. Even before the development of basic G- and R-banding techniques, CML was found to be associated with a persistent chromosomal abnormality, the Philadelphia (Ph) chromosome. Banding technology later showed the marker chromosome to be a translocation between the breakpoint cluster region (BCR) on chromosome 22q11.2 and the Abelson proto-oncogene (ABL) on chromosome 9q34. Further advances in cytogenetic and molecular biology have also contributed to the understanding, diagnosis, and treatment of CML. Fluorescent in situ hybridization (FISH) has revealed cryptic translocations in most cases of Ph-negative CML. Additional rare chromosomal variant translocations have been discovered as well.

The understanding of cytogenetic and molecular physiopathology of CML has led to the use of tyrosine kinase inhibitors as treatment for this disease with spectacular success. Over the 40 years since being identified as the first cytogenetic disease, CML has become the greatest success in translating the basic science of oncology into the treatment of patients with cancer.

In this review we will not only summarize the biology of CML, recent progress in the delineation of mechanisms and treatment strategies, but also we will discuss the laboratory tools used for diagnosing CML, for monitoring during treatment and for revealing point mutations and additional chromosomal abnormalities. In doing so, we will describe in detail our individual research on CML, identifying why and how these tests were performed to help to explain CML subgroups and clinical significance of additional chromosomal abnormalities.

The mechanisms for the formation of variant Philadelphia (Ph) translocations that occur in 5–10% of patients with chronic myeloid leukemia (CML) are not fully characterized. Studies on the prognosis of these variant translocations have yielded conflicting results, especially regarding imatinib outcome and the status of deletions on the derivative chromosome 9. To shed light on these controversial subjects, we sought to analyze all variant translocation cases presented at diagnosis and identified in our institution between the years 2001 and 2008. Of 336 CML patients who presented at diagnosis and were studied by conventional cytogenetics and fluorescence in situ hybridization (FISH), 25 patients (7.44%) exhibited variant Ph-rearrangements. All chromosomes could be implicated in variant Ph rearrangements, with 32 breakpoints defined. Their distribution was located preferentially in the CG-richest regions of the genome. Deletions on der(9) were observed in 15 of the 25 cases (60%), a greater proportion in typical Ph translocations (12–15%). Both one- and two-step mechanisms were encountered in our series, as well as multiple-step mechanisms, which originate more complex rearrangements. Higher prevalence was observed for the two-step mechanism (56%). Proper assessment of the prognostic significance of variant translocations requires better categorization of these translocations based on their mechanisms of genesis and 9q34 deletion status.