Manisha M Brahmbhatt, Pina J Trivedi and Prabhudas S Patel
Highly Complex Chromosomal Rearrangements in Patients with Chronic Myeloid Leukemia: An Indian Experience
During progression of chronic myeloid leukemia (CML) from the chronic to the accelerated phase and/or blast crisis, clonal evolution with nonrandom secondary aberrations such as +8, +Ph, i(17q), +19, -Y, +21, +17, and -7 are frequently observed. In 5-10% of cases with CML, variant or complex translocations (CT) are seen that may result in atypical fluorescence in situ hybridization (FISH) signal patterns. Complex chromosomal rearrangements (CCR) are rather rare, and the significance and frequency of different anomalies are poorly understood. The aim of this study was to identify the role of highly CCR (hCCR) in CML patients and also to determine the chromosomes and chromosomal regions which are involved in CCR at diagnosis and the frequency of nonrandom changes in a large series of 393 CML patients. Conventional cytogenetics was performed in 393 CML patients, out of that 8 patients showed highly complex chromosomal rearrangements. FISH and multicolor FISH (M- FISH) were also performed for complete characterization of karyotypes. More than three chromosomes were found to be involved in the hCCR. Minimum 4 and maximum 7 chromosomes were involved in hCCR. Besides chromosomes 9 and 22, most often involved in CCR were chromosomes 5, 10, 12 and 15 (x3); 1, 6, 11 and 17 (x2) and regions 5q, 10p, 12q and 15q (x3); 1q (x2). There were no recurrent complex translocations. Total 4 patients were treated with Imatinib Mesylate (IM), and only 2 patients showed complete hematologic response, whereas no cytogenetic response was achieved in any of them. Our data showed that the presence of hCCR is results in to poor prognosis. Therefore, we suggest that patients with variant translocations constitute a “warning” category in the imatinib era. The present findings also indicate the high genomic instability of the genome of malignant cells at chromosomal level. Precise determination of breakpoints involved in hCCR can give new dimension to the understanding of genetic mechanisms which may play role in leukemogenesis. The involvement of chromosomes other than 9 and 22 is not a random event but could depend on specific genomic features. The presence of several genes and/or miRNAs at the identified breakpoints suggests their potential involvement in the CML pathogenesis.
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