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Multiple myeloma gammopathies

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

Leukemia volume 33, pages 739–748 (2019)Cite this article

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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.

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Acknowledgements

This research is supported by the National Medical Research Council of Singapore grant NMRC/OFYIRG/0010/2016. WJC is supported by NMRC Singapore Translational Research (STaR) Investigatorship. This research is partly supported by the National Research Foundation Singapore and the Singapore Ministry of Education under the Research Centers of Excellence initiative as well as the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s Tier 3 grants, grant number MOE2014-T3-1-006.

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Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore

    Zhigang Xie, Sabrina Hui Min Toh & Wee Joo Chng

  2. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore

    Jing Yuan Chooi & Wee Joo Chng

  3. Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, 138668, Singapore

    Dongxiao Yang, Nurhidayah Binte Basri & Ying Swan Ho

  4. National University Cancer Institute, National University Health System, Singapore, 119228, Singapore

    Wee Joo Chng

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Xie, Z., Chooi, J.Y., Toh, S.H.M. et al. MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells. Leukemia 33, 739–748 (2019). https://doi.org/10.1038/s41375-018-0300-0

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