Investigating the role of TRIM33 in the DNA damage response in multiple Myeloma

Analysis of data from the publicly available CoMMpass dataset revealed around 12.3% of newly diagnosed MM patients to have a copy number loss of TRIM33, and these patients have a significantly increased frequency of chromosomal structural variants and poorer overall survival. TRIM33 shRNA knockdown was performed in two MM cell lines to investigate this loss in vitro. shTRIM33 cells exhibited increased endogenous DNA damage as shown by increased formation of 53BP1 foci and increased γH2AX expression indicating a potential DNA repair defect.

Furthermore shTRIM33 cells displayed increased phosphorylation of CHK1 and KAP1 indicative of activation of ATR and ATM kinases respectively. Importantly, shTRIM33 cells were sensitized to PARP inhibitor Olaparib and ATR inhibitor VE-821, and these compounds were synergistic with standard-of-care bortezomib. RNA-seq analysis revealed massive differential expression of genes associated with immunity/inflammation in shTRIM33 cells suggesting this may contribute to, or be a consequence of, the observed DNA repair defect.

To conclude, this study has identified a subgroup of MM patients with TRIM33 loss who display poor outcome and chromosomal instability, likely due to a defective DDR. In the future, PARP and ATR inhibitors may be potential therapy candidates for this high-risk subgroup.<br>