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

Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The translocation t(4;14)(p16;q32) is one of the most common translocation in MMs, affecting 15% of patients, and is associated with very poor prognosis. The histone methyltransferase (HMTase) MMSET is universally overexpressed in t(4;14) MM as a result of the t(4;14) translocation. MMSET is capable of producing 3 major isoforms, the full length MMSET II, short isoforms REIIBP and MMSET I. MMSET II has been suggested to play an important tumorigenic role in t(4;14) MM, but little is yet known about whether and how the MMSET short isoforms contribute to MM tumorigenesis. The aim of this study is to characterize MMSET I roles and determine its downstream targets in t(4;14) MM. In t(4;14) MM cells MMSET I knockdown with shRNAs induced cell apoptosis, reduced colony formation and inhibited tumorigenicity in vivo. We also found MMSET I knockdown decreased GLO1 expression, and ectopic MMSET I increased GLO1 expression, suggesting that MMSET I is an upstream regulator of GLO1. Further analysis indicated that MMSET I bound to GLO1 promoter region and depended on its C-terminus to regulate GLO1 expression. Our preliminary data suggested that MMSET I is an oncoprotein and could regulate GLO1 expression in t(4;14) multiple myeloma cells. Overall design: KMS11 cells were treated with shRNAs for 72 h. Total RNA was extracted by using the Qiagen RNeasy Mini kit (Germany). Gene expression was performed using the GeneChip™ Human Gene 2.0 ST Array (Affymetrix) following the manufacturer’s instructions. Data analysis was performed using GeneSpring software from Agilent Technologies.