@article{0fcf5ff9c2dc41beb3f5f6956e3b9243,
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.}",
note = "Funding Information: Evan J. Barnes received the Physician Scientist Career Development Award from the American Society of Haematology. Brian J. Druker is supported by the National Institutes of Health (NIH)/ National Cancer Institute (NCI) (R01 CA065823‐21). Cristina E. Tognon is supported by the NIH/NCI (R01 CA065823‐21; R01 CA214428‐04; U01 CA217862‐03). Daniel Bottomly, Beth Wilmot and Shannon K. McWeeney were supported by NIH/NCI (R01 CA065823‐21). Andy Kaempf is supported by NIH/NCI (R01 CA065823‐21). We would also like to acknowledge the important contributions of many additional laboratory members including Kara Johnson, Anna Resister Schultz, Steve Kurtz, Sunil Joshi, and Tamilla Nechiporuk. We would also like to give a special thanks to the Oregon Health and Science University (OHSU) School of Medicine and Human Investigations Program for their support during this project. We thank all of our patients for donating precious time and tissue. Funding Information: This manuscript contains original research, has not been previously published, and is not under consideration for publication elsewhere. Brian J. Druker serves on the Scientific Advisory Board for Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Vivid Biosciences, Celgene, the RUNX1 Research Program, Nemucore Medical Innovations, Recludix Pharma, Gilead Sciences (inactive), and Monojul (inactive); serves on the Novartis CML Molecular Monitoring Steering Committee; serves on the Advisory Boards and has ownership interest (including stock, patents, etc.) in Aptose Biosciences, Blueprint Medicines, EnLiven Therapuetics, Iterion Therapeutics, and GRAIL; is the Scientific Founder of MolecularMD (inactive, acquired by ICON); is a founder of VB Therapeutics; serves on the Board of Directors and has ownership interest in Amgen and Vincerx Pharma; serves on the Board of Directors for Burroughs Wellcome Fund and CureOne; and is an uncompensated Joint Steering Committee member for Beat AML LLS. Brian J. Druker has a sponsored research agreement with EnLiven Therapeutics, and clinical trial funding from Novartis, Bristol‐Myers Squibb, and Pfizer; receives royalties from Patent 6 958 335 (Novartis exclusive licence) and OHSU and Dana‐Farber Cancer Institute (one Merck exclusive licence and one CytoImage, Inc. exclusive licence). Cristina E. Tognon reports receiving commercial research support from Notable Labs and serves on their Scientific Advisory Board. The remaining authors declare no potential conflicts of interest. Funding Information: Evan J. Barnes received the Physician Scientist Career Development Award from the American Society of Haematology. Brian J. Druker is supported by the National Institutes of Health (NIH)/ National Cancer Institute (NCI) (R01 CA065823-21). Cristina E. Tognon is supported by the NIH/NCI (R01 CA065823-21; R01 CA214428-04; U01 CA217862-03). Daniel Bottomly, Beth Wilmot and Shannon K. McWeeney were supported by NIH/NCI (R01 CA065823-21). Andy Kaempf is supported by NIH/NCI (R01 CA065823-21). We would also like to acknowledge the important contributions of many additional laboratory members including Kara Johnson, Anna Resister Schultz, Steve Kurtz, Sunil Joshi, and Tamilla Nechiporuk. We would also like to give a special thanks to the Oregon Health and Science University (OHSU) School of Medicine and Human Investigations Program for their support during this project. We thank all of our patients for donating precious time and tissue. Publisher Copyright: {\textcopyright} 2022 British Society for Haematology and John Wiley & Sons Ltd.",
year = "2023",
month = feb,
doi = "10.1111/bjh.18515",
language = "English (US)",
volume = "200",
pages = "323--328",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",
number = "3",
}