Abstract 3487: Molecular clusters and functional drivers of IgM monoclonal gammopathies
Authors: Mondello Patrizia , Paludo Jonas , Novak Joseph , Wenzl Kerstin , Jalali Shahrzad , Krull Jordan , Braggio Esteban , Dasari Surendra , Manske Michelle , Abeykoon Jithma , Chanan-Khan Asher , Kyle Robert , Gertz Morie , Yang Zhi Zhang , Novak Anne , Ansell Stephen 
Published: June 2022

Abstract
IgM MGUS and Waldenstrom Macroglobulinemia (WM) represent a disease spectrum with highly dissimilar 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. To shed light on the biology that may account for the clinical differences, we used bone marrow (BM) CD19+/CD138+ sorted cells and matched BM plasma from 32 patients (pts) (7 IgM MGUS, 25 WM) and 5 healthy controls to perform the first comprehensive multiomics approach including whole exome sequencing, RNA seq, proteomics and metabolomics. Applying principal component analysis to gene expression profiling, most of WM pts clustered together, while a small subset of them grouped separately with MGUS pts, suggesting a biologic dichotomy within WM. The healthy controls formed a distinct group from most WM and MGUS. We then applied a non-negative matrix factorization consensus clustering to the gene expression data and identified three robust clusters. Cluster 1 (C1) included only WM pts, cluster 2 (C2) included both WM and MGUS pts, and cluster 3 (C3) included all controls as well as a small number of WM and MGUS pts. When mutations commonly identified in WM were analyzed, there was no difference among the three groups (excluding controls) in mutation burden of MYD88 L265P and CXCR4. Interestingly, aberrant expression of TNFAIP3 seemed a distinct feature of C1 as deletion of 6q (which encodes for TNFAIP3) and TNFAIP3 mutations were each significantly enriched in C1 (47%) compared to C2 (0%) and C3 (20%; p=0.04). Individual clusters associated with specific transcriptional signature and clinical features. While C1 displayed enrichment of cell growth, downregulation of inflammatory pathways (eg IL6 and IL8 signaling) and aggressive behavior, C2 showed increased inflammatory signaling and cell survival with indolent behavior. C3 had an intermediate feature with combined proliferative and inflammatory signatures. In accordance with the transcriptomic data, the hallmark of C1 was upregulation of proliferation-associated proteins (eg AKT, MAPK) and downregulation of inflammatory proteins (eg IL4, IL10) while the opposite was observed in C2. Once more, C3 confirmed intermediate features with combined upregulation of proliferation and inflammatory proteins. The metabolism was rewired towards fatty acid catabolism in C1, glycolysis in C2 and anabolism in C3. Accordingly, C1 showed undetectable concentration of 3-hydroxybutyric acid as opposed to C2 which had increased levels of malic and lactic acids, as end products of fatty acid oxidation and glycolysis respectively. Those metabolites had intermediate levels in C3. In conclusion, we identified three molecular clusters with distinct clinical, proteomic and metabolomic features, suggesting a potential biologic classification that may have therapeutic implications.
Citation Format: Patrizia Mondello, Jonas Paludo, Joseph Novak, Kerstin Wenzl, Shahrzad Jalali, Jordan Krull, Esteban Braggio, Surendra Dasari, Michelle Manske, Jithma Abeykoon, Asher Chanan-Khan, Robert Kyle, Morie Gertz, Zhi Zhang Yang, Anne Novak, Stephen Ansell. Molecular clusters and functional drivers of IgM monoclonal gammopathies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3487.