Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis.

Abstract

Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.

• Authors: Alexandra M Poos, Nina Prokoph, Moritz J Przybilla, Jan-Philipp Mallm, Simon Steiger, Isabelle Seufert, Lukas John, Stephan M Tirier, Katharina Bauer, Anja Baumann, Jennifer Rohleder, Umair Munawar, Leo Rasche, K Martin Kortüm, Nicola Giesen, Philipp Reichert, Stefanie Huhn, Carsten Müller-Tidow, Hartmut Goldschmidt, Oliver Stegle, Marc S Raab, Karsten Rippe, Niels Weinhold
• Journal: Blood (Blood) Vol. 142 Issue 19 Pg. 1633-1646 (11 09 2023) ISSN: 1528-0020 [Electronic] United States
• PMID: 37390336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 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.

Topics

• Humans
• Multiple Myeloma (drug therapy, genetics)
• Multiomics
• Mutation
• Transcriptome
• Tumor Microenvironment (genetics)