S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes

Abstract

Multiple myeloma (MM) is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to MM progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting MM progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent anti-myeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in MM.

scRNA-Seq and Bulk-Seq Analysis Identifies S100A9 Plasma Cells as a Potentially Effective Immunotherapeutic Agent for Multiple Myeloma

“… 41 Additionally, the S100A8/S100A9 protein produced by bone marrow neutrophils and monocytes regulates myeloma progression by promoting megakaryocyte expansion and angiogenesis. 42 However, it remains unclear whether plasma cells with high expression of S100A9 impact tumor immunity. In this study, we integrated scRNA-seq and Bulkseq to analyze the role of S100A9 plasma cells in MM patients.…”

Good Cop, Bad Cop: Profiling the Immune Landscape in Multiple Myeloma

“…Further, stage-specific differences in cytokine expression and megakaryocyte numbers were observed [182]. In mouse cell lines, megakaryocytes were shown to be necessary for MMPC growth in the BM, and this could be through IL-6 and APRIL [183,184]. IL-1β is produced by myeloid and megakaryocytic cells and myeloma cells and could induce osteoclast activity, mediate homing and adhesion of MMPCs in the BM, and consequently induce pro-inflammatory IL-6 signaling [185].…”