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Impact of the Breakpoint Region on the Leukemogenic Potential and the TKI Responsiveness of Atypical BCR-ABL1 Transcripts
- 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.
- Subjects :
- 0301 basic medicine
BCR-ABL1 fusion transcripts
RM1-950
Biology
Philadelphia chromosome
Leukemogenic
DC2
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
hemic and lymphatic diseases
medicine
Pharmacology (medical)
CML
nilotinib
Original Research
Pharmacology
ABL
Ponatinib
breakpoint cluster region
Imatinib
medicine.disease
Dasatinib
SH3
030104 developmental biology
Nilotinib
chemistry
TKIs
030220 oncology & carcinogenesis
Cancer research
Therapeutics. Pharmacology
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Frontiers in Pharmacology, Frontiers in Pharmacology, Vol 12 (2021)
- Accession number :
- edsair.doi.dedup.....c03d4413709da4a227c25ef4df6b036a