Abstract
BackgroundThe t(9;22)(q34;q11), generating the Philadelphia (Ph) chromosome, is found in more than 90% of patients with chronic myeloid leukemia (CML). As a result of the translocation, the 3' portion of the ABL1 oncogene is transposed from 9q34 to the 5' portion of the BCR gene on chromosome 22 to form the BCR/ABL1 fusion gene. At diagnosis, in 5-10% of CML patients the Ph chromosome is derived from variant translocations other than the standard t(9;22).ResultsWe report a molecular cytogenetic study of 452 consecutive CML patients at diagnosis, that revealed 50 cases identifying three main subgroups: i) cases with variant chromosomal rearrangements other than the classic t(9;22)(q34;q11) (9.5%); ii) cases with cryptic insertions of ABL1 into BCR, or vice versa (1.3%); iii) cases bearing additional chromosomal rearrangements concomitant to the t(9;22) (1.1%). For each cytogenetic group, the mechanism at the basis of the rearrangement is discussed.All breakpoints on other chromosomes involved in variant t(9;22) and in additional rearrangements have been characterized for the first time by Fluorescence In Situ Hybridization (FISH) experiments and bioinformatic analyses. This study revealed a high content of Alu repeats, genes density, GC frequency, and miRNAs in the great majority of the analyzed breakpoints.ConclusionsTaken together with literature data about CML with variant t(9;22), our findings identified several new cytogenetic breakpoints as hotspots for recombination, demonstrating that 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.
Highlights
The presence of several genes and/or miRNAs at the identified breakpoints suggests their potential involvement in the chronic myeloid leukemia (CML) pathogenesis
In 5-10% of CML patients, the 5'BCR/3'ABL1 fusion gene arises from complex variant rearrangements which
A detailed molecular cytogenetic characterization of 50 (11.1%) out of 452 chronic phase (CP) CML patients was carried out to define the precise breakpoints on chromosomes other than 9 and 22
Summary
FISH data Cytogenetic analysis and FISH experiments with specific BAC/PAC probes for the ABL1 and BCR genes allowed us to detect 50 (11.1%) out of 452 cases, that identify 3 main subgroups of CML patients showing variant t(9;22) rearrangements, the occurrence of cryptic insertions of the ABL1 in the BCR region (or vice versa), and the presence of additional chromosomal abnormalities, respectively (Table 1). 1. FISH data Cytogenetic analysis and FISH experiments with specific BAC/PAC probes for the ABL1 and BCR genes allowed us to detect 50 (11.1%) out of 452 cases, that identify 3 main subgroups of CML patients showing variant t(9;22) rearrangements, the occurrence of cryptic insertions of the ABL1 in the BCR region (or vice versa), and the presence of additional chromosomal abnormalities, respectively (Table 1). Conventional and molecular cytogenetic analysis showed 5 (1.1%) out of 452 CML cases bearing additional chromosomal rearrangements concomitant to the generation of the 5'BCR/3'ABL1 fusion gene (Table 1; Fig. 1G, H). Three subgroups of CML patients have been identified according to the chromosomal rearrangements detected by FISH experiments: cases showing variant t(9;22) rearrangements, patients characterized by cryptic insertions of the ABL1 into the BCR region (or vice versa), and cases bearing additional chromosomal abnormalities. The search for miRNAs revealed a different density from the expected value in 32 out of 58 (55%) breakpoint
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