Abstract
<div>Abstract<p>The bone marrow (BM) microenvironment actively promotes multiple myeloma pathogenesis, and therapies targeting both cancer cells and the niche are highly effective. We were interested in identifying novel signaling pathways supporting multiple myeloma–BM cross-talk. Mutations in the transmembrane receptor <i>Roundabout 1 (ROBO1)</i> were recently identified in patients with multiple myeloma; however, their functional consequences are uncertain. Through protein structure–function studies, we discovered that ROBO1 is necessary for multiple myeloma adhesion to BM stromal and endothelial cells and that <i>ROBO1</i> knockout (KO) compromises BM homing and engraftment in a disseminated mouse model. <i>ROBO1</i> KO significantly decreases multiple myeloma proliferation <i>in vitro</i> and intra- and extramedullary tumor growth <i>in vivo</i>. Mechanistically, the ROBO1 C-terminus is cleaved in a ligand-independent fashion and is sufficient to promote multiple myeloma proliferation. Vice versa, mutants lacking the cytoplasmic domain, including the human-derived G674* truncation, act dominantly negative. Interactomic and RNA-sequencing studies suggest that ROBO1 may be involved in RNA processing, supporting further studies.</p>Significance:<p>ROBO1 is highly expressed in t(4;14) multiple myeloma and supports homing and dissemination to the BM niche. <i>ROBO1</i> knockout causes reduced tumor growth in intramedullary and extramedullary myeloma animal models, while the ROBO1 C-terminus is cleaved in multiple fragments and it is necessary and sufficient to sustain myeloma proliferation.</p></div>
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