MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells.

Abstract

Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. T(4;14) MM overexpresses multiple myeloma SET domain-containing protein (MMSET). MMSET has three major isoforms: the full-length form MMSET II and the short isoforms REIIBP and MMSET I. Here we show that the short isoform MMSET I is an oncoprotein that promoted cell survival and tumorigenesis in vitro and in vivo. Gene expression array analysis indicated that MMSET I increased glyoxalase I (GLO1) expression. Chromatin immunoprecipitation (ChIP) coupled with qPCR indicated that MMSET I bound upstream of the GLO1 transcription start site. Ectopic overexpression of MMSET I or its mutants showed MMSET I depended on its C terminus to regulate GLO1 expression. GLO1 knockdown (KD) induced apoptosis and reduced colony formation. MMSET I or GLO1 KD reduced the levels of anti-apoptosis factors such as MCL1 and BCL2. Ectopic overexpression of GLO1 resulted in the significant rescue of KMS11 cells from MMSET I KD-induced apoptosis and glycolysis inhibition. This suggested that GLO1 may be of functional importance target downstream of MMSET I. Cumulatively, our study suggests that MMSET I is an oncoprotein and potential therapeutic target for t(4;14) MM.