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

Author

Listed:
  • Romanos Sklavenitis-Pistofidis

    (Dana-Farber Cancer Institute
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
    Harvard Medical School)

  • Yoshinobu Konishi

    (Dana-Farber Cancer Institute
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
    Harvard Medical School)

  • Daniel Heilpern-Mallory

    (Dana-Farber Cancer Institute
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard)

  • 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
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
    Harvard Medical School)

  • Zachary R. Hunter

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • 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
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
    Harvard Medical School)

  • Katherine Towle

    (Dana-Farber Cancer Institute)

  • Laura Hevenor

    (Dana-Farber Cancer Institute)

  • Rizwan Romee

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Edward L. Briercheck

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Eric L. Smith

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Christine-Ivy Liacos

    (School of Medicine)

  • Efstathios Kastritis

    (School of Medicine)

  • Meletios A. Dimopoulos

    (School of Medicine)

  • Steven P. Treon

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Gad Getz

    (Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Irene M. Ghobrial

    (Dana-Farber Cancer Institute
    Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard
    Harvard Medical School)

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.

Suggested Citation

  • 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. Haradhva, 2025. "Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56323-w
    DOI: 10.1038/s41467-025-56323-w
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    References listed on IDEAS

    as
    1. Tarek H. Mouhieddine & Adam S. Sperling & Robert Redd & Jihye Park & Matthew Leventhal & Christopher J. Gibson & Salomon Manier & Amin H. Nassar & Marzia Capelletti & Daisy Huynh & Mark Bustoros & Rom, 2020. "Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    2. S. Kasar & J. Kim & R. Improgo & G. Tiao & P. Polak & N. Haradhvala & M. S. Lawrence & A. Kiezun & S. M. Fernandes & S. Bahl & C. Sougnez & S. Gabriel & E. S. Lander & H. T. Kim & G. Getz & J. R. Brow, 2015. "Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    3. Lili Gu & David Casserly & Gareth Brady & Susan Carpenter & Adrian P. Bracken & Katherine A. Fitzgerald & Leonie Unterholzner & Andrew G. Bowie, 2022. "Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Rebecca Boiarsky & Nicholas J. Haradhvala & Jean-Baptiste Alberge & Romanos Sklavenitis-Pistofidis & Tarek H. Mouhieddine & Oksana Zavidij & Ming-Chieh Shih & Danielle Firer & Mendy Miller & Habib El-, 2022. "Single cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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