Genetic alterations of SENP6 disrupt DNA repair and proteostasis conferring sensitivity to proteasome inhibition in multiple myeloma

Targeting of the ubiquitin-proteasome system (UPS) remains a mainstay in the treatment of multiple myeloma (MM). Hyperactivation of the closely related SUMO pathway is implicated in disease progression and associated with poor prognosis. Here we investigated the functional imbalance of aberrant SUMOylation in MM by analyzing the large CoMMpass dataset for molecular alterations associated with SUMO pathway regulation. SENP6 and SENP7, key SUMO proteases, were significantly downregulated in patients with high SUMO pathway signatures. Recurrent loss of SENP6, a negative regulator of SUMOylation, was directly linked to adverse prognosis across all disease stages. SENP6 reconstitution markedly reduced cellular growth kinetics in SENP6-deficient MM, indicating a functional role for SENP6 as a tumor suppressor. Mechanistically, SENP6 loss resulted in the accumulation of DNA damage and misfolded proteins, thereby activating the unfolded protein response, increasing reliance on proteasomal degradation, and driving synthetic lethality to therapeutic proteasome inhibition. Together, we establish SENP6 as a biologically relevant biomarker and provide a mechanistic rationale for the clinical efficacy of proteasome inhibitors in the prognostically unfavorable subgroup of SENP6-deficient MM patients.