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Chronic Myeloid Leukemia (CML) is a hematological disorder characterized by the clonal expansion of a hematopoietic stem cell carrying the Philadelphia chromosome that juxtaposes the  BCR  and  ABL1  genes. The ensuing  BCR-ABL1  chimeric oncogene is characterized by a breakpoint region that generally involves exons 1, 13 or 14 in  BCR  and exon 2 in  ABL1 . Additional breakpoint regions, generating uncommon  BCR-ABL1  fusion transcripts, have been detected in various CML patients. However, to date, the impact of these infrequent transcripts on  BCR-ABL1 -dependent leukemogenesis and sensitivity to tyrosine kinase inhibitors (TKIs) remain unclear. We analyzed the transforming potential and TKIs responsiveness of three atypical  BCR-ABL1  fusions identified in CML patients, and of two additional  BCR-ABL1  constructs with lab-engineered breakpoints. We observed that modifications in the DC2 domain of BCR and SH3 region of ABL1 affect BCR-ABL1 catalytic efficiency and leukemogenic ability. Moreover, employing immortalized cell lines and primary CD34-positive progenitors, we demonstrate that these modifications lead to reduced BCR-ABL1 sensitivity to imatinib, dasatinib and ponatinib but not nilotinib. We conclude that BCR-ABL1 oncoproteins displaying uncommon breakpoints involving the DC2 and SH3 domains are successfully inhibited by nilotinib treatment.

Impact of the Breakpoint Region on the Leukemogenic Potential and the TKI Responsiveness of Atypical BCR-ABL1 Transcripts