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<p>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. <i>MYD88</i>-mutant tumors show transcriptional heterogeneity, which can be distilled in a molecular classification, including a <i>DUSP22</i>/<i>CD9</i>-positive subtype, and progression signatures which differentiate IgM MGUS from overt WM and can help advance WM research and clinical practice.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月10日

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  • 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,
  • Irene M. Ghobrial

摘要

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.