Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia.
Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia.
复制标题
DOI：
10.1158/2159-8290.cd-16-0237
复制
发表时间：
2016-10
期刊：
影响因子：
28.2
通讯作者：
Armstrong SA
中科院分区：
文献类型：
--
作者：
Kühn MW;Song E;Feng Z;Sinha A;Chen CW;Deshpande AJ;Cusan M;Farnoud N;Mupo A;Grove C;Koche R;Bradner JE;de Stanchina E;Vassiliou GS;Hoshii T;Armstrong SA
同源异型盒（HOX）蛋白和受体酪氨酸激酶FLT 3在急性髓性白血病（AML）中经常高度表达和突变。在几乎所有携带核磷酸蛋白（NPM 1）基因突变的AML中发现异常HOX表达，并且在这些病例中约60%伴随有FLT 3突变。很少有人知道突变型NPM 1（NPM 1 mut）细胞如何维持异常的基因表达。在这里，我们证明了组蛋白修饰剂MLL 1和DOT 1 L控制HOX和FLT 3在NPM 1 mut AML中的表达和分化。使用CRISPR-Cas9基因组编辑结构域筛选，我们显示NPM 1 mut AML异常依赖于MLL 1中的menin结合位点。menin-MLL 1蛋白相互作用的药理学小分子抑制在NPM 1 mut AML的人类和小鼠模型中具有显著的抗白血病活性。menin-MLL 1和DOT 1 L的组合药理学抑制导致HOX和FLT 3表达的显著抑制、分化的诱导和对NPM 1 mut白血病的上级活性。
Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR-Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacological small-molecule inhibition of the menin-MLL1 protein interaction had profound anti-leukemic activity in human and murine models of NPM1mut AML. Combined pharmacological inhibition of menin-MLL1 and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia.