Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors.

Autor:	Thompson ER; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia., Nguyen T; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia., Kankanige Y; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia., Markham JF; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia., Anderson MA; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; and.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia., Handunnetti SM; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia., Thijssen R; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; and., Yeh PS; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia., Tam CS; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia., Seymour JF; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia., Roberts AW; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; and.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia., Westerman DA; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia., Blombery P; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2022 Jan 25; Vol. 6 (2), pp. 503-508.
DOI:	10.1182/bloodadvances.2021006211
Abstrakt:	The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations. We also report the first observation of established BCL2 resistance mutations in a patient with mantle cell lymphoma (MCL) following PD on sequential monotherapy, implicating BCL2 as a venetoclax resistance mechanism in MCL. Taken together, these data reveal the significant clonal complexity of CLL and MCL progression on TAs at the nucleotide level and confirm the presence of multiple, clonally independent, mechanisms of TA resistance within each individual disease context. (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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