Secondary fusion proteins as a mechanism of BCR::ABL1 kinase-independent resistance in chronic myeloid leukaemia.
Evan J BarnesChristopher A EideAndy KaempfDaniel BottomlyKyle A RomineBeth WilmotDominick SaundersShannon K McWeeneyCristina E TognonBrian J DrukerPublished in: British journal of haematology (2022)
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.
Keyphrases
- chronic myeloid leukemia
- tyrosine kinase
- end stage renal disease
- genome wide identification
- single cell
- bone marrow
- acute myeloid leukemia
- dendritic cells
- chronic kidney disease
- ejection fraction
- poor prognosis
- signaling pathway
- acute lymphoblastic leukemia
- dna methylation
- adverse drug
- protein kinase
- case control
- bioinformatics analysis