Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia

Romanos Sklavenitis-Pistofidis, Yoshinobu Konishi, Daniel Heilpern-Mallory, Ting Wu, Nicholas Tsakmaklis, Michelle P. Aranha, Zachary R. Hunter, Alaa K. Ali, Junko Tsuji, Nicholas J. Haradhvala, Elizabeth D. Lightbody, Katherine Towle, Laura Hevenor, Rizwan Romee, Edward L. Briercheck, Eric L. Smith, Christine-Ivy Liacos, Efstathios Kastritis, Meletios A. Dimopoulos, Steven P. Treon, Gad Getz and Irene M. Ghobrial ()
Additional contact information
Romanos Sklavenitis-Pistofidis: Dana-Farber Cancer Institute
Yoshinobu Konishi: Dana-Farber Cancer Institute
Daniel Heilpern-Mallory: Dana-Farber Cancer Institute
Ting Wu: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
Nicholas Tsakmaklis: Dana-Farber Cancer Institute
Michelle P. Aranha: Dana-Farber Cancer Institute
Zachary R. Hunter: Dana-Farber Cancer Institute
Alaa K. Ali: Dana-Farber Cancer Institute
Junko Tsuji: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
Nicholas J. Haradhvala: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
Elizabeth D. Lightbody: Dana-Farber Cancer Institute
Katherine Towle: Dana-Farber Cancer Institute
Laura Hevenor: Dana-Farber Cancer Institute
Rizwan Romee: Dana-Farber Cancer Institute
Edward L. Briercheck: Dana-Farber Cancer Institute
Eric L. Smith: Dana-Farber Cancer Institute
Christine-Ivy Liacos: School of Medicine
Efstathios Kastritis: School of Medicine
Meletios A. Dimopoulos: School of Medicine
Steven P. Treon: Dana-Farber Cancer Institute
Gad Getz: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
Irene M. Ghobrial: Dana-Farber Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Waldenstrom’s Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that is preceded by an asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor and immune cells from 30 patients with AWM/WM, 26 patients with Smoldering Myeloma, and 23 healthy donors. Despite their early stage, patients with AWM present extensive immune dysregulation, including in normal B cells, with disease-specific immune hallmarks. Patient T and NK cells show systemic hypo-responsiveness to interferon, which improves with interferon administration and may represent a therapeutic vulnerability. MYD88-mutant tumors show transcriptional heterogeneity, which can be distilled in a molecular classification, including a DUSP22/CD9-positive subtype, and progression signatures which differentiate IgM MGUS from overt WM and can help advance WM research and clinical practice.

Date: 2025
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DOI: 10.1038/s41467-025-56323-w

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