Molecular Clusters and Tumor-Immune Drivers of IgM Monoclonal Gammopathies

Patrizia Mondello, Jonas Paludo, Joseph P. Novak, Kerstin Wenzl, Zhi Zhang Yang, Shahrzad Jalali, Jordan E. Krull, Esteban Braggio, Surendra Dasari, Michelle K. Manske, Jithma A. Abeykoon, Vivekananda Sarangi, Prashant Kapoor, Aneel Paulus, Craig B. Reeder, Sikander Ailawadhi, Asher A. Chanan-Khan, Robert A. Kyle, Morie A. Gertz, Anne J. NovakStephen M. Ansell

Research output: Contribution to journalArticlepeer-review


Purpose: IgM monoclonal gammopathy of undetermined significance (MGUS) and Waldenstr€om macroglobulinemia (WM) represent a disease spectrum with highly varied therapeutic management, ranging from observation to chemoimmunotherapy. The current classification relies solely on clinical features and does not explain the heterogeneity that exists within each of these conditions. Further investigation is warranted to shed light on the biology that may account for the clinical differences. Experimental Design: We used bone marrow (BM) clonal CD19þ and/or CD138þ sorted cells, matched BM supernatant, and peripheral blood serum from 32 patients (7 MGUS, 25 WM) to perform the first multi-omics approach including whole-exome sequencing, RNA sequencing, proteomics, metabolomics, and mass cytometry. Results: We identified three clusters with distinct pathway activation, immune content, metabolomic, and clinical features. Cluster 1 included only patients with WM and was characterized by transcriptional silencing of genes involved in cell cycle and immune response, enrichment of mitochondrial metabolism, infiltration of senescent T effector memory cells, and aggressive clinical behavior. Genetic/structural alterations of TNFAIP3 were distinct events of this cluster. Cluster 2 comprised both MGUS and WM patients with upregulation of inflammatory response, senescence and glycolysis signatures, increased activated T follicular helper and T regulatory cells, and indolent clinical behavior. Cluster 3 also included both MGUS and WM patients and exhibited intermediate features, including proliferative and inflammatory signaling, as well as glycolysis and mitochondrial metabolism. Conclusions: We have identified three distinct molecular clusters, suggesting a potential biologic classification that may have therapeutic implications.

Original languageEnglish (US)
Pages (from-to)957-970
Number of pages14
JournalClinical Cancer Research
Issue number5
StatePublished - Mar 1 2023

ASJC Scopus subject areas

  • General Medicine


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