Secondary fusion proteins as a mechanism of BCR :: ABL1 kinase‐independent resistance in chronic myeloid leukaemia

Autor: Evan J. Barnes, Christopher A. Eide, Andy Kaempf, Daniel Bottomly, Kyle A. Romine, Beth Wilmot, Dominick Saunders, Shannon K. McWeeney, Cristina E. Tognon, Brian J. Druker
Rok vydání: 2022
Předmět:
Zdroj: British Journal of Haematology. 200:323-328
ISSN: 1365-2141
0007-1048
DOI: 10.1111/bjh.18515
Popis: Drug resistance in chronic myeloid leukaemia (CML) may occur via mutations in the causative BCR::ABL1 fusion or BCR::ABL1-independent mechanisms. We analysed 48 patients with BCR::ABL1-independent resistance for the presence of secondary fusion genes by RNA sequencing. We identified 10 of the most frequently detected secondary fusions in 21 patients. Validation studies, cell line models, gene expression analysis and drug screening revealed differences with respect to proliferation rate, differentiation and drug sensitivity. Notably, expression of RUNX1::MECOM led to resistance to ABL1 tyrosine kinase inhibitors in vitro. These results suggest secondary fusions contribute to BCR::ABL1-independent resistance and may be amenable to combined therapies.
Databáze: OpenAIRE
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