Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Nat Chem Biol. 2012 Jan 29;8(3):277-84. doi: 10.1038/nchembio.773.
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.
易位涉及混合谱系白血病（MLL）基因，导致预后极差的人类急性白血病。MLL 融合蛋白的致癌活性严重依赖于其与 menin 的直接相互作用，menin 是多发性内分泌肿瘤（MEN1）基因的产物。在这里，我们提出了据我们所知，第一个 menin-MLL 融合蛋白相互作用的小分子抑制剂，它们以纳摩尔亲和力特异性结合 menin。这些化合物通过下调 MLL 融合蛋白致癌活性所需的靶基因的表达，有效地逆转 MLL 融合蛋白介导的白血病转化。它们还选择性地阻断增殖并诱导携带 MLL 易位的白血病细胞凋亡和分化。这些化合物的鉴定为更好地理解 MLL 介导的白血病发生提供了新的工具，并代表了研究 menin 作为 MLL 融合蛋白致癌辅助因子的作用的新方法。我们的发现还突出了一种新的治疗策略，用于治疗具有 MLL 重排的侵袭性白血病。
