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

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

doi:10.1111/bjh.18515

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

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

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	323-328
Number of pages	6
Journal	British Journal of Haematology
Volume	200
Issue number	3
DOIs	https://doi.org/10.1111/bjh.18515
State	Published - Feb 2023

Keywords

CML
chromosomal rearrangements
drug resistance

ASJC Scopus subject areas

Hematology

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10.1111/bjh.18515

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title = "Secondary fusion proteins as a mechanism of BCR::ABL1 kinase-independent resistance in chronic myeloid leukaemia",

abstract = "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.",

keywords = "CML, chromosomal rearrangements, drug resistance",

author = "Barnes, {Evan J.} and Eide, {Christopher A.} and Andy Kaempf and Daniel Bottomly and Romine, {Kyle A.} and Beth Wilmot and Dominick Saunders and McWeeney, {Shannon K.} and Tognon, {Cristina E.} and Druker, {Brian J.}",

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year = "2023",

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doi = "10.1111/bjh.18515",

language = "English (US)",

volume = "200",

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AU - Barnes, Evan J.

AU - Eide, Christopher A.

AU - Kaempf, Andy

AU - Bottomly, Daniel

AU - Romine, Kyle A.

AU - Wilmot, Beth

AU - Saunders, Dominick

AU - McWeeney, Shannon K.

AU - Tognon, Cristina E.

AU - Druker, Brian J.

PY - 2023/2

Y1 - 2023/2

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AB - 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.

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KW - chromosomal rearrangements

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

Abstract

Keywords

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