Impact of Clonal Hematopoiesis on the Carcinogenic Process of Multiple Myeloma

Clonal hematopoiesis (CH), a phenomenon linked to aging, correlates with inflammation and myeloid malignancies. Here, we explore the interaction of CH, with terminally differentiated lymphoid malignancy, and multiple myeloma (MM). Analysis of CH in clinical cohorts revealed a higher prevalence among MM patients and a lower deep response to proteasome inhibitors. By utilizing the bone marrow samples from MM patients with CH, single-cell transcriptome analyses indicated frequent interaction between CH and MM cells, mediated by CCR10-CCL2, resulting in the upregulation of the MAPK pathway and angiogenesis, findings corroborated by exosome RNA analysis. Conditioned media from TET2 knockdown macrophages significantly enhanced MM cell proliferation compared to that from wild-type cells, an effect reversible by a CCR10 inhibitor. Our results underscore the pivotal role of TET2 CH in driving CCR10-high myeloma progression through paracrine oncogenic effects via exosomal interactions on CCR10, suggesting its potential as a therapeutic target.