Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical UniversityAbstractはじめに多発性骨髄腫は形質細胞が腫瘍化した造血器腫瘍である．主な病巣は骨髄内にあり，造血障害，骨破壊や大量の異常免疫グロブリン産生による腎障害などを発症する．患者数は造血器腫瘍の中で2番目に多く，国内約2万人，海外約80万人．発症頻度は全人口10万人当り約2名であるが70歳代では20名近くに増加するため，高齢者人口の増加に伴う医療ニーズの増大が予想される．発症に伴う骨痛など患者の苦痛も極めて大きく，治療費も高額であるため，疾患克服の社会的意義は非常に大き自治医科大学分子病態治療研究センター幹細胞制御研究部― 200 ―The prognosis for multiple myeloma (MM) has continued to improve with the development of a series of novel molecular targeted drugs over time. However, the prognosis remains poor for cases with high-risk chromosomal abnormalities. Of such abnormalities, t(4;14) is the second most common, occurring in 15% of patients with MM. MM cells carrying t(4;14) strongly express histone methyltransferase with a SET domain, called MMSET, making them resistant to drugs against MM. Therefore, MMSET is an effective therapeutic target for MM carrying t(4;14). Subsequently, we performed high-throughput screening for small molecule inhibitors of MMSET using small molecule compound libraries and identified RK-0080552 (RK-552) as a first-in-class MMSET inhibitor. RK-552 was significantly cytotoxic against t(4;14)-positive MM compared to t(4;14)-negative MM cells in vitro and in vivo via transcriptional suppression of the IRF4 gene. This coincided with a decrease in H3K36 methylation at the gene. Moreover, RK-552 acted additively with pomalidomide in vitro and prolonged the survival of recipient mice without side effects. These results suggest that RK-552 is the first clinically relevant MMSET inhibitor with safety and specific cytotoxicity to MM cells carrying t(4;14). Our study also provide a molecular basis and rationale for the inclusion in current treatment strategies, therefore, the clinical use of RK-552 may significantly improve the treatment outcome of MM with t(4;14).ヒストンメチル化酵素MMSET阻害剤の開発Development of histone methyltransferase MMSET inhibitors菊池 次郎Jiro Kikuchi
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