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'BCR/3'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.