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Compared with other B\u2010cell neoplasms, the lymphoplasmacytic clone in WM can be rather small, limiting our understanding of clonal expansion. We applied an integrative approach using single\u2010cell RNA with B\u2010cell receptor (BCR) sequencing, the assay for transposase\u2010accessible chromatin, and whole\u2010genome sequencing to characterize the tumor clone in patients with IgM MGUS, smoldering WM (SWM), and symptomatic WM (WM). IgM MGUS and low\u2010 or intermediate\u2010risk SWM harbored multiple B\u2010cell clones compared to WM.\n                    <jats:italic>CD9<\/jats:italic>\n                    ,\n                    <jats:italic>JCHAIN<\/jats:italic>\n                    ,\n                    <jats:italic>RASSF6,<\/jats:italic>\n                    and\n                    <jats:italic>DUSP22<\/jats:italic>\n                    were the main markers of the dominant B\u2010cell clone at gene expression and chromatin activity levels, with\n                    <jats:italic>CD9<\/jats:italic>\n                    preferentially expressed in plasma cell\u2010like tumor cells.\n                    <jats:italic>POU2F2<\/jats:italic>\n                    had high activity in the tumor clone and was linked to\n                    <jats:italic>CD9<\/jats:italic>\n                    regulatory regions.\n                    <jats:italic>MYD88<\/jats:italic>\n                    and\n                    <jats:italic>IGLL5<\/jats:italic>\n                    mutations, mainly associated with the mutational signature SBS5, were present in minor clones, whereas the\n                    <jats:italic>MYD88<\/jats:italic>\n                    mutation was also detected in nonexpanded B\u2010cells. The 6q deletion was present in tumor cells from high\u2010risk patients, which harbored fitness advantage over copy\u2010neutral tumor cells. Coding mutations clustered tumor and minor clones from oligoclonal patients and were associated with abnormal transcriptional programs. The B\u2010cell clones also showed enriched predicted interactions with monocytes. Our integrative single\u2010cell approach reveals the importance of clone size in IgM gammopathy and identifies key markers promoting clonal expansion.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70456","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T19:11:25Z","timestamp":1789240285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clonotypic characterization defines B\u2010cell drivers of clonal expansion and intratumor heterogeneity in IgM monoclonal gammopathies"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1752-3081","authenticated-orcid":false,"given":"David F.","family":"Moreno","sequence":"first","affiliation":[{"name":"Amyloidosis and Myeloma Unit, Department of Hematology Hospital Cl\u00ednic de Barcelona, University of Barcelona Barcelona Spain"},{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer 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