Genomic segmental duplications on the basis of the t(9;22) rearrangement in chronic myeloid leukemia

Abstract

A crucial role of segmental duplications (SDs) of the human genome has been shown in chromosomal rearrangements associated with several genomic disorders. Limited knowledge is yet available on the molecular processes resulting in chromosomal rearrangements in tumors. The t(9;22)(q34;q11) rearrangement causing the 5 0 BCR/3 0 ABL gene formation has been detected in more than 90% of cases with chronic myeloid leukemia (CML). In 10-18% of patients with CML, genomic deletions were detected on der(9) chromosome next to translocation breakpoints. The molecular mechanism triggering the t(9;22) and deletions on der(9) is still speculative. Here we report a molecular cytogenetic analysis of a large series of patients with CML with der(9) deletions, revealing an evident breakpoint clustering in two regions located proximally to ABL and distally to BCR, containing an interchromosomal duplication block (SD_9/22). The deletions breakpoints distribution appeared to be strictly related to the distance from the SD_9/22. Moreover, bioinformatic analyses of the regions surrounding the SD_9/22 revealed a high Alu frequency and a poor gene density, reflecting genomic instability and susceptibility to rearrangements. On the basis of our results, we propose a three-step model for t(9;22) formation consisting of alignment of chromosomes 9 and 22 mediated by SD_9/22, spontaneous chromosome breakages and misjoining of DNA broken ends.

Identification of copy number alterations by array comparative genomic hybridization in patients with late chronic or accelerated phase chronic myeloid leukemia treated with imatinib mesylate

“…Patients started on IM at early chronic phase, however, do not show an adverse association with this deletion [20,21]. The extent of copy number loss on der(9) is variable and may range from a few hundred kilobases to many megabases, and sometimes involving the entire short arm of chromosome 9 [22,23]. We localized the smallest overlapping region of imbalance among the five patients with 9q34 loss to a 1 Mb region proximal to ABL1.…”

PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications

“…A recent example is segmental duplications (SDs), which are elements of 1-400 kB regions of demonstrating >90% homology (Eichler, 2001;Sharp et al, 2006;Khurana et al, 2010). These SDs are thought to be recombinational hotspots that facilitate genomic rearrangements and copy number changes in tumors (Squire et al, 2003;Braude et al, 2006;Hastings et al, 2009;Albano et al, 2010;Chen et al, 2010;El-Hattab et al, 2010;Martin et al, 2010). For example, SDs map close to the ABL and BCR rearrangement breakpoints on chromosomes 9 and 22 that are associated with fusion translocation in chronic myeloid leukemia (Albano et al, 2010).…”

“…These SDs are thought to be recombinational hotspots that facilitate genomic rearrangements and copy number changes in tumors (Squire et al, 2003;Braude et al, 2006;Hastings et al, 2009;Albano et al, 2010;Chen et al, 2010;El-Hattab et al, 2010;Martin et al, 2010). For example, SDs map close to the ABL and BCR rearrangement breakpoints on chromosomes 9 and 22 that are associated with fusion translocation in chronic myeloid leukemia (Albano et al, 2010). Such SDs are also suspected of predisposing to constitutional microdeletion syndromes (Mefford et al, 2007;Descartes et al, 2008;Mefford and Eichler, 2009;Ballif et al, 2010;Bengesser et al, 2010).…”

Novel chromosomal translocation (17;22)(q12;q12) in a case of myelodisplastic syndrome characterized with signs of hemolytic anemia at presentation

“…The presence of SDs within both chromosomal breakpoint regions suggests that these nucleotide elements, which are very important during the evolution of species (Marques-Bonet and Eichler, 2009) and the genesis of genomic disorders and hematological cancer (Albano et al, 2010) could trigger one or more of the mutational events in the present MDS case. In addition, the translocation t (17;22) was accompanied by a deletion of 640 kb on chromosome 22, within which some important genes map: LIF (leukemia inhibitory factor), OSM (oncostatin M precursor), SF3A1 (splicing factor 3a, subunit 1), and DUSP18 (dual specificity phosphatase 18) are few of all the genes mapping there (specifically 30 known genes).…”

“…The G-banding analysis of bone marrow metaphases revealed the following karyotype: 46,XX,t(17;22)(q12;q12) (Tefferi & Vardiman, 2009)/47,idem,+8 (Albano et al, 2010)/46,XX (Albano et al, 2010) (Figs. 1A and B).…”