A multiomic analysis of Waldenström macroglobulinemia defines distinct disease subtypes
Abstract
Abstract We carried out a single-cell multiomic analysis on a series of MYD88-mutated Waldenström macroglobulinemia (WM) patients and identified 2 distinct subtypes of disease, memory B-cell (MBC)–like and plasma cell (PC)–like, based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully toward a PC and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the MBC stage, upregulates key MBC genes, and is characterized by upregulated B-cell receptor and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling. In contrast, the PC-like subtype can partially differentiate toward a PC, upregulates key PC genes, has enhanced NF-κB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin with sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the 2 disease subtypes were validated further using hierarchical clustering of bulk RNA-sequencing data from a secondary set of patients. The biological significance of the subtypes was further established using whole-genome sequencing, in which it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype, and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as 2 disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features, with potential implications for WM treatment strategies.
Article Details
Authors (25)
Dylan C. Gagler
1Multiple Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Health, New York, NY
Hussein Ghamlouch
4Hématopoïèse et Immunologie, Unité de Recherche 4666, Université de Picardie Jules Verne, Amiens, France
Di Zhang
Patrick Blaney
1Multiple Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Health, New York, NY
Avital Tenenbaum
1NYU Langone Health, Multiple Myeloma Research Program, New York, United States
James Langton
1NYU Langone Health, Multiple Myeloma Research Program, New York, United States
Marine Armand
2Gustave Roussy, la Recherche Médicale, Villejuif, France
Alexandre Eeckhoutte
2Gustave Roussy, la Recherche Médicale, Villejuif, France
Amina Joudat
2Gustave Roussy, la Recherche Médicale, Villejuif, France
Michael Degaud
1Gustave Roussy, Villejuif, France
Michela Esposito
Department of Medical Physics and Biomedical Engineering
Gaurav Varma
4NYU Langone Health, New York, United States
Yubao Wang
Department of Cancer Biology, Dana-Farber Cancer Institute
Sanghoon Lee
Sanxiong Liu
HHMI, New York University Langone Health
Oscar Lahoud
11. Multiple Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Medical Center, New York, United States
David Kaminetzky
11. Multiple Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Medical Center, New York, United States
Marc Braunstein
11. Multiple Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Medical Center, New York, United States
Louis Williams
Florence Nguyen-Khac
31APHP, Paris, France
Brian Walker
1Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, United States
Damien Roos-Weil
5Drug Resistance in Hematological Malignancies Team, Centre de Recherche des Cordeliers, Université Paris Cité, INSERM UMRS 1138, Sorbonne Université, Paris, France
Faith E. Davies
1Multiple Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Health, New York, NY
Olivier A. Bernard
4Université Paris-Saclay, INSERM, Gustave Roussy, Dynamique Moléculaire de la Transformation Hématopoïétique, Villejuif, France
Gareth J. Morgan