Loss of Mll5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation
Loss of Mll5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation
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DOI：
10.1182/blood-2008-02-162263
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发表时间：
2009-02-12
期刊：
影响因子：
20.3
通讯作者：
Aparicio, Samuel A.
中科院分区：
文献类型：
--
作者：
Heuser, Michael;Yap, Damian B.;Aparicio, Samuel A.
MLL 5是果蝇Trithorax相关（SET）结构域和植物同源结构域（PHD）结构域的不同成员，其含有染色质调节剂，参与分化期间转录“记忆”的调节。人MLL 5位于染色体7 q22上，其在髓性白血病中经常缺失，表明在造血中可能起作用。为了解决这个问题，我们在鼠M115基因座中产生了功能丧失的等位基因（M115（tm 1Apa））。与其他M11基因不同，M115（tm 1Apa）纯合子小鼠是可存活的，但显示免疫和造血缺陷。首先，M115（tm 1Apa）纯合子小鼠表现出对自发性眼部感染的易感性增加，与中性粒细胞功能的细胞自主性损伤相关。第二，M115（tm 1Apa/tm 1Apa）小鼠表现出轻度红细胞生成障碍。第三，M115（tm 1Apa/tm 1Apa）造血干细胞（HSC）在正常条件下和当受到NUP 98-HOXA 10的自我更新刺激时都具有受损的竞争性再增殖能力。第四，M115（tm 1Apa）纯合HSC显示出对DNA去甲基化诱导的分化（5-氮脱氧胞苷）的显著敏感性。总之，我们的数据表明，MLL 5参与终末髓样分化和调控HSC自我更新的机制，涉及DNA甲基化。这些数据保证了MLL 5表达水平作为骨髓增生异常综合征和白血病患者中去甲基化剂反应的预测标志物的研究，并将MLL 5鉴定为正常造血的关键调节因子。（血。2009; 113：1432-1443）
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. (Blood. 2009; 113: 1432-1443)