Abstract 383: APOBEC3B is induced by activation of DNA repair pathway and modulates the survival and treatment response in human multiple myeloma

Constitutive genomic complexity, ongoing DNA damage, and accumulating mutations are observed with progression from monoclonal gammopathy of undetermined significance (MGUS) to active multiple myeloma (MM) to relapsed/refractory disease. Apolipoprotein B mRNA editing catalytic polypeptide-like 3B (APOBEC3B), a DNA cytosine deaminase in cancer mutagenesis, is recently linked to sub-clonal diversification, intra-tumor heterogeneity, and tumor evolution in MM. We here studied the upstream mechanisms of APOBEC3B dysregulation and further defined functional consequences of molecular manipulation of APOBEC3B in MM cells. We first asked whether APOBEC3B levels are altered in MM cells upon treatments with Melphalan (Mel), an alkylating agent used to treat MM which is known to induce replication stress, or with ionizing radiation (IR). Sub-lethal doses of Mel or IR induce APOBEC3B transcript and protein expression in a dose- and time-dependent manner in MM cell lines (n=7), associated with phosphorylation of γH2AX. Significantly, Bortezomib (btz), even at sub-lethal doses triggering DNA damage signaling, induced APOBEC3B expression in multiple MM cell lines. Next, inhibition of ATR or ATM activation pathway significantly decreased Mel- or IR or btz-induced APOBEC3B, suggesting that replication stress induced by Mel, IR, or btz activates ATM/ATR-dependent APOBEC3B induction. We used gene-specific CRISPR knock out (KO), shRNA knockdown (KD), and inducible-shRNA KD to study the functional impact of perturbation of APOBEC3B in MM cells. Both KO and KD of APOBEC3B decreased growth and survival in multiple MM cell lines sensitive or resistant to dexamethasone or lenalidomide. APOBEC3B inhibition significantly enhanced growth arrest followed by apoptosis in MM cells, suggesting that increased APOBEC3B levels contribute to MM cell survival. We next analyzed available data sources for MM cell lines from Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer, which include microarray gene expression and drug sensitivity information. APOBEC3B expression negatively correlates with MM cell sensitivity to JQ1, a BET inhibitor which inhibit MM cell growth and survival in vitroand in vivo. Importantly, in MM cell lines which are relatively resistant to pomalidomide and JQ1 than other cell lines, APOBEC3B KD by its shRNA enhances sensitivity to both drugs. Taken together, our findings provide new insights into the role of APOBEC3B in triggering cytidine deaminase-induced mutagenesis associated with progression of disease. Furthermore, DNA replication stress triggered by Mel, IR, or btz upregulates APOBEC3B expression, which in turn confers drug resistance. The role of APOBEC in disease pathogenesis and progression, coupled with its role mediating drug resistance, suggest potential utility of targeting APOBEC3B in novel MM therapies. Citation Format: Lijie Xing, Jiye Liu, Liang Lin, Shih-Feng Cho, Kenneth Wen, Tengteng Yu, Gang An, Ligui Qiu, Kenneth Anderson, Yu-Tzu Tai. APOBEC3B is induced by activation of DNA repair pathway and modulates the survival and treatment response in human multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 383.