The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis
The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis
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DOI：
10.1016/j.cell.2005.09.025
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发表时间：
2005-10-21
期刊：
影响因子：
64.5
通讯作者：
Cleary, ML
中科院分区：
文献类型：
--
作者：
Yokoyama, A;Somervaille, TCP;Cleary, ML
混合谱系白血病（MLL）蛋白是一种组蛋白甲基转移酶，在急性白血病的临床和生物学特征子集中发生突变。MLL通常与一组高度保守的辅因子结合形成一种大分子复合物，其中包括menin，menin是MEN 1肿瘤抑制基因的产物，在遗传性和散发性内分泌肿瘤中突变。我们在这里证明，致癌MLL融合蛋白保持稳定的能力，通过高亲和力，氨基末端，保守的结合基序与menin，这种相互作用是必需的MLL介导的白血病的启动。此外，menin对于维持MILL相关的而不是其他癌基因诱导的髓样转化是必需的。急性基因切除menin逆转异常Hox基因表达介导的MLL-menin启动子相关复合物，并特别废除分化停滞和致癌特性的MLL转化白血病母细胞。这些结果表明，人类癌蛋白是严重依赖于直接的物理相互作用与肿瘤抑制蛋白的致癌活性，验证一个潜在的目标分子治疗，并建议中央作用menin改变表观遗传功能的造血系统癌症的发病机制。
The Mixed-Lineage Leukemia (MLL) protein is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. MLL normally associates with a cohort of highly conserved cofactors to form a macromolecular complex that includes menin, a product of the MEN1 tumor suppressor gene, which is mutated in heritable and sporadic endocrine tumors. We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis. Furthermore, menin is essential for maintenance of MILL-associated but not other oncogene induced myeloid transformation. Acute genetic ablation of menin reverses aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes, and specifically abrogates the differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity, validate a potential target for molecular therapy, and suggest central roles for menin in altered epigenetic functions underlying the pathogenesis of hematopoietic cancers.