SETD7 is a novel therapeutic target for multiple myeloma with t(11;14)+

Abstract The prognosis of patients with multiple myeloma (MM) harboring t(11;14) is controversial. However, the latest retrospective analysis revealed that t(11;14) is a poor prognostic factor. MM with t(11;14) is resistant to key drugs other than immunomodulatory drugs (IMiDs); therefore, treatment for MM with t(11;14) refractory to IMiDs are an unmet medical need. This study searched for novel therapeutic targets within SET-domain family histone methyltransferases. SETD7 was highly expressed in MM patients harboring t(11;14) and was associated with inferior survival. The genetic knockdown and pharmacologic inhibition of SETD7 significantly suppressed the growth of MM cell lines harboring t(11;14). Chromatin immunoprecipitation sequence analysis of SETD7 revealed many peaks, over 70% of which were localized in the vicinity of transcription start sites including the ARID1A, PRDM1, and c-FOS genes. PFI2, a SETD7 inhibitor, significantly inhibited the growth of MM cells harboring t(11;14) and a combination of PFI2 and pomalidomide additively inhibited growth by down-regulating the ARID1A/IRF4/MYC axis in vitro and in vivo. These results suggest that SETD7 is a novel therapeutic target for MM harboring t(11;14). Our study provides a rationale for the efficacy of SETD7 inhibitor-based therapy for patients with MM harboring t(11;14).