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MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells. (Leukemia, Nov 18)

Xie Z1, Chooi JY2, Toh SHM1, Yang D3, Basri NB3, Ho YS3, Chng WJ4,5,6.

Author information
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
3Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, 138668, Singapore.
4Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. mdccwj@nus.edu.sg.
5Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore. mdccwj@nus.edu.sg.
6National University Cancer Institute, National University Health System, Singapore, 119228, Singapore. mdccwj@nus.edu.sg.

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.

PMID: 30470837