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

Authors :
Michele Massimino
Elena TirrĂ²
Stefania Stella
Livia Manzella
Maria Stella Pennisi
Chiara Romano
Silvia Rita Vitale
Adriana Puma
Cristina Tomarchio
Sandra Di Gregorio
Agostino Antolino
Francesco Di Raimondo
Paolo Vigneri
Source :
Frontiers in Pharmacology, Frontiers in Pharmacology, Vol 12 (2021)
Publication Year :
2021

Abstract

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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Frontiers in Pharmacology, Frontiers in Pharmacology, Vol 12 (2021)
Accession number :
edsair.doi.dedup.....c03d4413709da4a227c25ef4df6b036a