Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia
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 wi...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56323-w |
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| author | 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 |
| author_facet | 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 |
| author_sort | Romanos Sklavenitis-Pistofidis |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c62f07b7c8c149ef8acc46413d18417f |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c62f07b7c8c149ef8acc46413d18417f2025-08-20T02:59:54ZengNature PortfolioNature Communications2041-17232025-02-0116111910.1038/s41467-025-56323-wSingle-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s MacroglobulinemiaRomanos Sklavenitis-Pistofidis0Yoshinobu Konishi1Daniel Heilpern-Mallory2Ting Wu3Nicholas Tsakmaklis4Michelle P. Aranha5Zachary R. Hunter6Alaa K. Ali7Junko Tsuji8Nicholas J. Haradhvala9Elizabeth D. Lightbody10Katherine Towle11Laura Hevenor12Rizwan Romee13Edward L. Briercheck14Eric L. Smith15Christine-Ivy Liacos16Efstathios Kastritis17Meletios A. Dimopoulos18Steven P. Treon19Gad Getz20Irene M. Ghobrial21Department of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteBroad Institute of Massachusetts Institute of Technology (MIT) and HarvardDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteBroad Institute of Massachusetts Institute of Technology (MIT) and HarvardBroad Institute of Massachusetts Institute of Technology (MIT) and HarvardDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Clinical Therapeutics, National and Kapodistrian University of Athens, School of MedicineDepartment of Clinical Therapeutics, National and Kapodistrian University of Athens, School of MedicineDepartment of Clinical Therapeutics, National and Kapodistrian University of Athens, School of MedicineDepartment of Medical Oncology, Dana-Farber Cancer InstituteBroad Institute of Massachusetts Institute of Technology (MIT) and HarvardDepartment of Medical Oncology, Dana-Farber Cancer InstituteAbstract 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.https://doi.org/10.1038/s41467-025-56323-w |
| spellingShingle | 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 Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia Nature Communications |
| title | Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia |
| title_full | Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia |
| title_fullStr | Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia |
| title_full_unstemmed | Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia |
| title_short | Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia |
| title_sort | single cell rna sequencing defines distinct disease subtypes and reveals hypo responsiveness to interferon in asymptomatic waldenstrom s macroglobulinemia |
| url | https://doi.org/10.1038/s41467-025-56323-w |
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