融合蛋白
融合基因
染色体易位
癌症研究
白血病
生物
基因
癌基因蛋白质类
门1
基因表达调控
遗传学
多发性内分泌肿瘤
重组DNA
作者
Jolanta Grembecka,Shihan He,Aibin Shi,Trupta Purohit,Andrew G. Muntean,Roderick J. Sorenson,Hollis D. Showalter,Marcelo J. Murai,Amalia Marie Belcher,Thomas Hartley,Jay L. Hess,Tomasz Cierpicki
摘要
MLL fusion genes often encode leukemogenic proteins that depend on interaction with menin, a component of the MLL SET1-like histone methyltransferase complex. MI-2 and MI-3 are the first small molecules that can block menin–MLL fusion protein interaction and their oncogenic effects in cells. Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin–MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein–mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.
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