Abstract
Multiple myeloma (MM) is a heterogeneous disease characterized by significant genomic instability. Recently, a causal role for the AID/APOBEC deaminases in inducing somatic mutations in myeloma has been reported. We have identified APOBEC/AID as a prominent mutational signature at diagnosis with further increase at relapse in MM. In this study, we identified upregulation of several members of APOBEC3 family (A3A, A3B, A3C, and A3G) with A3G, as one of the most expressed APOBECs. We investigated the role of APOBEC3G in MM and observed that A3G expression and APOBEC deaminase activity is elevated in myeloma cell lines and patient samples. Loss-of and gain-of function studies demonstrated that APOBEC3G significantly contributes to increase in DNA damage (abasic sites and DNA breaks) in MM cells. Evaluation of the impact on genome stability, using SNP arrays and whole genome sequencing, indicated that elevated APOBEC3G contributes to ongoing acquisition of both the copy number and mutational changes in MM cells over time. Elevated APOBEC3G also contributed to increased homologous recombination activity, a mechanism that can utilize increased DNA breaks to mediate genomic rearrangements in cancer cells. These data identify APOBEC3G as a novel gene impacting genomic evolution and underlying mechanisms in MM.
Highlights
Multiple myeloma (MM) is a plasma cell malignancy associated with a marked genomic instability
ABOBEC3G is dysregulated in multiple myeloma We evaluated the expression of APOBEC family of proteins in myeloma patient samples and cell lines
The deaminase activity was significantly elevated in patient MM cells and MM cell lines, compared to normal plasma cells from healthy donors (NPC), suggesting significantly elevated APOBEC activity is in myeloma (Fig. 1B)
Summary
Multiple myeloma (MM) is a plasma cell malignancy associated with a marked genomic instability. The clonal heterogeneity plays a critical role in development of resistance to treatment and relapse [8, 9]. The high DNA damage and dysregulated repair are among important factors contributing to genomic instability. Previous data has established the role of dysregulated homologous recombination (HR) activity in the ongoing genomic rearrangements and instability in MM [1]. Data from our and other laboratories have demonstrated that APOBEC mutational signature is prevalent in MM cell genome [3,4,5,6]. The APOBEC mutational signature correlates with sub-clonal diversity in myeloma [4, 7]
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