Journal article
Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy
R Thijssen, L Tian, MA Anderson, C Flensburg, A Jarratt, AL Garnham, JS Jabbari, H Peng, TE Lew, CE Teh, Q Gouil, A Georgiou, T Tan, TM Djajawi, CS Tam, JF Seymour, P Blombery, DHD Gray, IJ Majewski, ME Ritchie Show all
Blood | ELSEVIER | Published : 2022
Abstract
Venetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with eventual loss of efficacy. A spectrum of subclonal genetic changes associated with VEN resistance has now been described. To fully understand clinical resistance to VEN, we combined single-cell short- and long-read RNA-sequencing to reveal the previously unappreciated scale of genetic and epigenetic changes underpinning acquired VEN resistance. These appear to be multilayered. One layer comprises changes in the BCL2 family of apoptosis regulators, e..
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Awarded by Silicon Valley Community Foundation
Funding Acknowledgements
This work was supported by scholarships, fellowships, and grants from the Australian National Health and Medical Research Council (NHMRC: Program Grants 1016647, 1113577 to A.W.R., 1016701, 1113133 to D.C.S.H., Fellowships 1089072 to C.E.T., 1090236 and 1158024 to D.H.D.G., 1079560 to A.W.R., 1043149, 1156024 to D.C.S.H., Investigator Grant 1177718 to M.A.A., 1174902 to A.W.R.), the Leukemia & Lymphoma Society of America (Fellowship 5467-18 to R.T., Specialized Center of Research (SCOR) grant 7015-18 to A.W.R. and D.C.S.H.), The Australian Research Council (Discovery Project 200102903 to M.E.R.),Cure Cancer and Cancer Australia (grant 1186003 to R.T.), Victorian Cancer Agency (MCRF grant 15018 to I.J.M. and A.W.R., MCRF20026Fellowship to C.E.T.), Cancer Council Victoria (grants-in-aid 1146518and 1102104 to D.H.D.G. and 1124178 to I.J.M.), the University of Melbourne (MIRS and MIFRS scholarships to L.T., H.P., and T.M.D.),grants from Snowdome Foundation (M.A.A. and P.B.), Wilson Centre for Lymphoma Genomics (P.B.), Victorian Comprehensive Cancer Centre(support for mass cytometry), Perpetual Impact Philanthropy Founding(IPAP2019/1437 to C.E.T.), the Chan Zuckerberg Initiative DAF (an advised fund of Silicon Valley Community Foundation, grant number 2019-002443 to M.E.R.), and the Australian Cancer Research Foundation. This work was made possible through Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIISS