Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
Leukemia. 2019 Mar;33(3):739-748. doi: 10.1038/s41375-018-0300-0. Epub 2018 Nov 23.
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.
多发性骨髓瘤（MM）的特征是反复出现的染色体易位。T（4；14）MM 过表达多发性骨髓瘤 SET 域蛋白（MMSET）。MMSET 有三种主要的亚型：全长形式的 MMSET II 和短亚型 REIIBP 和 MMSET I。在这里，我们表明短亚型 MMSET I 是一种癌蛋白，它在体外和体内促进细胞存活和肿瘤发生。基因表达谱分析表明，MMSET I 增加了甘油醛-3-磷酸脱氢酶（GLO1）的表达。染色质免疫沉淀（ChIP）与 qPCR 表明 MMSET I 结合在 GLO1 转录起始位点的上游。过表达 MMSET I 或其突变体表明，MMSET I 依赖其 C 末端来调节 GLO1 的表达。GLO1 的敲低（KD）诱导细胞凋亡并减少集落形成。MMSET I 或 GLO1 KD 降低了抗凋亡因子如 MCL1 和 BCL2 的水平。过表达 GLO1 导致 KMS11 细胞从 MMSET I KD 诱导的细胞凋亡和糖酵解抑制中显著恢复。这表明 GLO1 可能是 MMSET I 下游的功能重要靶标。总之，我们的研究表明，MMSET I 是一种癌蛋白，是 t（4；14）MM 的潜在治疗靶点。
