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; Irene M Ghobrial

doi:10.1038/s41467-025-56323-w

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

Nat Commun. 2025 Feb 10;16(1):1480. doi: 10.1038/s41467-025-56323-w.

Authors

Romanos Sklavenitis-Pistofidis^#^{1

2

3}, Yoshinobu Konishi^#^{1

2

3}, Daniel Heilpern-Mallory^{1

2}, Ting Wu², Nicholas Tsakmaklis¹, Michelle P Aranha^{1

2

3}, Zachary R Hunter^{1

3}, Alaa K Ali¹, Junko Tsuji², Nicholas J Haradhvala², Elizabeth D Lightbody^{1

2

3}, Katherine Towle¹, Laura Hevenor¹, Rizwan Romee^{1

3}, Edward L Briercheck^{1

3}, Eric L Smith^{1

3}, Christine-Ivy Liacos⁴, Efstathios Kastritis⁴, Meletios A Dimopoulos⁴, Steven P Treon^{1

3}, Gad Getz^{2

3

5}, Irene M Ghobrial^{6

7

8}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
³ Harvard Medical School, Boston, MA, USA.
⁴ Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
⁵ Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.
⁷ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. irene_ghobrial@dfci.harvard.edu.
⁸ Harvard Medical School, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.

^# Contributed equally.

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.

MeSH terms

Aged
Aged, 80 and over
B-Lymphocytes / immunology
Disease Progression
Female
Humans
Immunoglobulin M / immunology
Interferons*
Killer Cells, Natural / immunology
Male
Middle Aged
Mutation
Myeloid Differentiation Factor 88 / genetics
Sequence Analysis, RNA
Single-Cell Analysis*
T-Lymphocytes / immunology
Waldenstrom Macroglobulinemia* / drug therapy
Waldenstrom Macroglobulinemia* / genetics
Waldenstrom Macroglobulinemia* / immunology

Substances

Interferons
Myeloid Differentiation Factor 88
Immunoglobulin M
MYD88 protein, human

Abstract

MeSH terms

Substances

Grants and funding