Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Blood. 2011 Dec 15;118(25):6544-52. doi: 10.1182/blood-2010-11-317909. Epub 2011 Oct 19.
The mixed-lineage leukemia (MLL) H3K4 methyltransferase protein, and the heterodimeric RUNX1/CBFβ transcription factor complex, are critical for definitive and adult hematopoiesis, and both are frequently targeted in human acute leukemia. We identified a physical and functional interaction between RUNX1 (AML1) and MLL and show that both are required to maintain the histone lysine 4 trimethyl mark (H3K4me3) at 2 critical regulatory regions of the AML1 target gene PU.1. Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation. Furthermore, a subset of previously uncharacterized frame-shift and missense mutations at the N terminus of AML1, found in MDS and AML patients, impairs its interaction with MLL, resulting in loss of the H3K4me3 mark within PU.1 regulatory regions, and decreased PU.1 expression. The interaction between MLL and AML1 provides a mechanism for the sequence-specific binding of MLL to DNA, and identifies RUNX1 target genes as potential effectors of MLL function.
混合谱系白血病（MLL）H3K4 甲基转移酶蛋白和异二聚体 RUNX1/CBFβ 转录因子复合物对于确定和成人造血至关重要，并且两者都是人类急性白血病的常见靶点。我们确定了 RUNX1（AML1）和 MLL 之间的物理和功能相互作用，并表明两者都需要维持 AML1 靶基因 PU.1 的 2 个关键调节区域的组蛋白赖氨酸 4 三甲基标记（H3K4me3）。与 CBFβ 类似，我们表明 MLL 与 AML1 结合，从而阻止其蛋白酶体依赖性降解。此外，在 MDS 和 AML 患者中发现的 AML1 氨基末端的一组先前未表征的移码和错义突变，会损害其与 MLL 的相互作用，导致 PU.1 调节区域内 H3K4me3 标记丢失，并降低 PU.1 表达。MLL 和 AML1 之间的相互作用为 MLL 与 DNA 的序列特异性结合提供了一种机制，并确定 RUNX1 靶基因作为 MLL 功能的潜在效应子。
