OAB-010: Gain(1q) promotes mitochondrial oxidative phosphorylation and suppresses interferon response and tumor immunity in multiple myeloma and other human cancers

Introduction Gain of chromosome 1q is a recurrent genomic feature of many human tumors and is present in 33-48% of newly diagnosed MMs (NDMM). Analogous to deletion of 17p, + 1q can occur as a secondary genetic event in all MM subtypes, and is associated with poor prognosis. Although uncommon in precursor stages such as monoclonal gammopathy of undetermined significance (MGUS), the prevalence of +1q rises significantly in symptomatic MM, and at relapse, suggesting roles in malignant transformation and treatment escape. The molecular mechanisms underlying these associations remain poorly understood. Here, we report an analysis of the transcriptional consequences of +1q in single MM cells and in bulk tumor samples. Methods To define the molecular consequences of + 1q at a cellular level, we performed single cell RNA-sequencing (scRNA-seq) and single-cell inferred CNV (sciCNV) analysis of primary MM bone marrow samples. This provided paired DNA/RNA omics information within single cells. From MM samples containing intra-clonal populations with and without +1q we directly examined the effects of +1q on gene expression. The effects of +1q were delineated using intra-clonal isogenic sibling cells lacking +1q as controls. We validated our findings using 10 tumor cohorts, including 2 MM cohorts representing >1300 NDMM patients and 8 non-MM cohorts representing 3,915 patients with other malignancies. Results From these studies we show that primary MM cells with +1q significantly upregulate mitochondrial oxidative phosphorylation (OXPHOS), causing increased reactive oxygen species and reduced energy stress, compared with isogenic sibling cells without +1q. Despite increased OXPHOS, +1q cells do not appear to experience increased hypoxia nor reduced glycolysis, suggesting that they continue to benefit from aerobic glycolysis (Warburg metabolism). At the same time +1q MM cells overexpress ADAR and suppress IFN type 1 and 2 responses, repressing tumor immunity. Overexpression of CD46, CFH, CFHR1, CHFR5, ARPC5 and SELL from +1q further suppress pathways involved in tumor immune recognition, particularly by complement and antibodies. MM tumors overexpressing MYC are enriched amongst +1q samples, with MYC co-operating with MCL1 to promote mitochondrial oxidative phosphorylation, leading to apparent enrichment of a MYC gene expression signature in +1q samples, though MYC itself is not increased by +1q. From MM registry data, +1q cooperates with MYC to promote OXPHOS, and OXPHOS strongly predicts patient survival, particularly in high-risk t(4;14) and del(17p) subtypes. Examination of 8 non-MM tumor cohorts reveals that other human cancers with +1q similarly upregulate OXPHOS and MYC programs and/or suppress tumor immunity (IFN-g and -a responses, complement pathways and allograft rejection). Conclusion Overall, from these multi-omic analyses we identify critical reprogramming events in MM and other human cancers that arise from +1q and that predict patient survival.