Kobrossy Laila, Xu Weiyi, Zhang Chunling, Feng Wenyi, Turner Christopher E, Cosgrove Michael S
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, United States.
Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, New York, United States.
J Biol Chem. 2024 Nov;300(11):107825. doi: 10.1016/j.jbc.2024.107825. Epub 2024 Sep 27.
Our understanding of acute leukemia pathology is heavily dependent on 11q23 chromosomal translocations involving the mixed lineage leukemia-1 (MLL1) gene, a key player in histone H3 lysine 4 (H3K4) methylation. These translocations result in MLL1-fusion (MLL1) proteins that are thought to drive leukemogenesis. However, the mechanism behind increased H3K4 trimethylation in MLL1-leukemic stem cells (MLL1-LSCs), following loss of the catalytic SET domain of MLL1 (known for H3K4 monomethylation and dimethylation) remains unclear. In our investigation, we introduced a homozygous loss-of-function point mutation in MLL1 within human-induced pluripotent stem cells. This mutation mimics the histone methylation, gene expression, and epithelial-mesenchymal transition phenotypes of MLL1-LSCs-without requiring a translocation or functional WT MLL1. The mutation caused a genome-wide redistribution of the H3K4 trimethyl mark and upregulated LSC-maintenance genes like HoxA9-A13, Meis1, and the HOTTIP long noncoding RNA. Epithelial-mesenchymal transition markers such as ZEB1, SNAI2, and HIC-5 were also increased leading to enhanced cellular migration and invasiveness. These observations underscore the essential role of MLL1's enzymatic activity in restraining the cascade of epigenetic changes associated with the gene-activating H3K4 trimethylation mark, which we show may be catalyzed by mislocalized SETd1a H3K4 trimethyltransferase in the absence of MLL1's enzymatic activity. Challenging existing models, our findings imply that MLL1-induced leukemias arise from a dominant-negative impact on MLL1's histone methyltransferase activity. We propose targeting SETd1a in precision medicine as a new therapeutic approach for MLL1-associated leukemias.
我们对急性白血病病理学的理解在很大程度上依赖于涉及混合谱系白血病-1（MLL1）基因的11q23染色体易位，MLL1基因是组蛋白H3赖氨酸4（H3K4）甲基化的关键参与者。这些易位产生MLL1融合（MLL1）蛋白，被认为可驱动白血病发生。然而，在MLL1白血病干细胞（MLL1-LSCs）中，MLL1的催化SET结构域（以H3K4单甲基化和二甲基化而闻名）缺失后，H3K4三甲基化增加背后的机制仍不清楚。在我们的研究中，我们在人诱导多能干细胞中引入了MLL1的纯合功能丧失点突变。该突变模拟了MLL1-LSCs的组蛋白甲基化、基因表达和上皮-间质转化表型，而无需易位或功能性野生型MLL1。该突变导致H3K4三甲基标记在全基因组范围内重新分布，并上调了如HoxA9-A13、Meis1和HOTTIP长链非编码RNA等维持LSC的基因。上皮-间质转化标志物如ZEB1、SNAI2和HIC-5也增加，导致细胞迁移和侵袭增强。这些观察结果强调了MLL1酶活性在抑制与基因激活的H3K4三甲基化标记相关的表观遗传变化级联中的重要作用，我们发现，在缺乏MLL1酶活性的情况下，这可能由错误定位的SETd1a H3K4三甲基转移酶催化。挑战现有模型，我们的研究结果表明，MLL1诱导的白血病源于对MLL1组蛋白甲基转移酶活性的显性负性影响。我们建议在精准医学中靶向SETd1a，作为治疗MLL1相关白血病的一种新的治疗方法。
