Heuser Michael, Yap Damian B, Leung Malina, de Algara Teresa Ruiz, Tafech Alaeddin, McKinney Steven, Dixon John, Thresher Rosemary, Colledge Bill, Carlton Mark, Humphries R Keith, Aparicio Samuel A
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Blood. 2009 Feb 12;113(7):1432-43. doi: 10.1182/blood-2008-06-162263. Epub 2008 Oct 14.
MLL5 is a divergent member of the Drosophila Trithorax-related (SET) domain and plant homeodomain (PHD) domain-containing chromatin regulators that are involved in the regulation of transcriptional "memory" during differentiation. Human MLL5 is located on chromosome 7q22, which frequently is deleted in myeloid leukemias, suggesting a possible role in hemopoiesis. To address this question, we generated a loss-of-function allele (Mll5(tm1Apa)) in the murine Mll5 locus. Unlike other Mll genes, Mll5(tm1Apa) homozygous mice are viable but display defects in immunity and hematopoiesis. First, Mll5(tm1Apa) homozygous mice show increased susceptibility to spontaneous eye infections, associated with a cell-autonomous impairment of neutrophil function. Second, Mll5(tm1Apa/tm1Apa) mice exhibit a mild impairment of erythropoiesis. Third, Mll5(tm1Apa/tm1Apa) hematopoietic stem cells (HSCs) have impaired competitive repopulating capacity both under normal conditions and when subjected to self-renewal stimulation by NUP98-HOXA10. Fourth, Mll5(tm1Apa) homozygous HSCs show a dramatic sensitivity to DNA demethylation-induced differentiation (5-azadeoxycytidine). Taken together, our data show that MLL5 is involved in terminal myeloid differentiation and the regulation of HSC self-renewal by a mechanism that involves DNA methylation. These data warrant investigation of MLL5 expression levels as a predictive marker of demethylating-agent response in patients with myelodysplastic syndromes and leukemias and identify MLL5 as a key regulator of normal hematopoiesis.
MLL5是果蝇类三胸蛋白相关（SET）结构域和含植物同源结构域（PHD）结构域的染色质调节因子中的一个不同成员，这些调节因子参与分化过程中转录“记忆”的调控。人类MLL5位于7号染色体的q22区域，该区域在髓系白血病中经常缺失，提示其在造血过程中可能发挥作用。为了解决这个问题，我们在小鼠Mll5基因座中产生了一个功能缺失等位基因（Mll5(tm1Apa)）。与其他Mll基因不同，Mll5(tm1Apa)纯合小鼠是存活的，但在免疫和造血方面表现出缺陷。首先，Mll5(tm1Apa)纯合小鼠对自发性眼部感染的易感性增加，并伴有中性粒细胞功能的细胞自主性损伤。其次，Mll5(tm1Apa/tm1Apa)小鼠表现出轻度的红细胞生成受损。第三，Mll5(tm1Apa/tm1Apa)造血干细胞（HSC）在正常条件下以及受到NUP98-HOXA10的自我更新刺激时，其竞争性重建能力受损。第四，Mll5(tm1Apa)纯合HSC对DNA去甲基化诱导的分化（5-氮杂脱氧胞苷）表现出显著的敏感性。综上所述，我们的数据表明MLL5通过涉及DNA甲基化的机制参与终末髓系分化和HSC自我更新的调控。这些数据值得对MLL5表达水平进行研究，以作为骨髓增生异常综合征和白血病患者对去甲基化药物反应的预测标志物，并确定MLL5是正常造血的关键调节因子。
