2024 - DEFICIENCY OF THE NOVEL TUMOR SUPPRESSOR C15ORF65 CAUSES MULTIPLE MYELOMA AND PLASMA CELL MALIGNANCY

Abstract

The previously uncharacterized locus C15orf65 (murine Gm5918) is diminutive, yet highly conserved within and beyond the animal kingdom. We show that it encodes a heterochromatin-associated protein with a hydrophobic pocket and an aromatic cage in its domain of unknown function 4490 (DUF4490) that facilitate its action as a tumor suppressor for multiple myeloma and plasma cell malignancy. Hematopoietic loss of Gm5918 in mice results in the development of transplantable MM at high penetrance between 1-2 years of age. M-spikes developed in the animals as early as 2-3 months before death while Gm5918deficient kidneys showed light chain amyloidosis. 18F PET-CT of animals upon serum M-spike development revealed solitary medullary plasmacytomas or extensive skeletal remodeling, which we found to be accompanied by extramedullary disease on necropsy. Colony forming unit assays and serial competitive transplantation show the defect to be cell intrinsic and cytokine independent after malignant transformation, while IL-7 inducible before disease onset. CD138+ cells from sick animals showed derepression of PRC2 and H3K27me3 targets, and we observed reduced H3K27me3 in tumor-derived cell lines. C15orf65 homodimerizes and co-immunoprecipitates with histone H3 and EED, identifying it as a new class of histone-binding scaffold protein for PRC2-mediated methylation of H3K27. In human MM patients, low C15orf65 correlates with aggressive disease, short time to progression, and increased mortality. Re-expressing C15orf65 in human MM1.R cell lines inhibits growth and establishment post-passaging, while expression of DUF4490-mutant C15orf65 reverses the phenotype. We propose naming C15orf65 SCaffold for HIStone Modification 1 (SCHISM1) and the previously uncharacterized DUF4490 family as a Histone Tail Targeting PRC Scaffold (HTTPS) domain.