The Chromatin Regulator CHD8 Is a Context-Dependent Mediator of Cell Survival in Murine Hematopoietic Malignancies

Aberrant chromatin regulation is a frequent driver of leukemogenesis. Mutations in chromatin regulators often result in more stem-like cells that seed a bulk leukemic population. Inhibitors targeting these proteins represent an emerging class of therapeutics, and identifying further chromatin regulators that promote disease progression may result in additional drug targets. We identified the chromatin-modifying protein CHD8 as necessary for cell survival in a mouse model of BCR-Abl+ B-cell acute lymphoblastic leukemia. This disease has a poor prognosis despite treatment with kinase inhibitors targeting BCR-Abl. Although implicated as a risk factor in autism spectrum disorder and a tumor suppressor in prostate and lung cancer, the mechanism of CHD8’s activity is still unclear and has never been studied in the context of hematopoietic malignancies. Here we demonstrate that depletion of CHD8 in B-ALL cells leads to cell death. While multiple B cell malignancies were dependent on CHD8 expression for survival, T cell malignancies displayed milder phenotypes upon CHD8 knockdown. In addition, ectopic expression of the Notch1 intracellular domain in a T cell malignancy partially alleviated the detrimental effect of CHD8 depletion. Our results demonstrate that CHD8 has a context-dependent role in cell survival, and its inhibition may be an effective treatment for B lymphoid malignancies.

染色质调控异常是白血病发生的常见驱动因素。染色质调节因子的突变往往会催生更多干细胞样细胞，进而形成大量白血病细胞群体。靶向此类蛋白的抑制剂属于新兴治疗手段，而进一步发掘可促进疾病进展的染色质调节因子，有望为白血病治疗带来更多药物靶点。我们在BCR-ABL阳性B细胞急性淋巴细胞白血病（BCR-Abl+ B-cell acute lymphoblastic leukemia）的小鼠模型中，确认染色质修饰蛋白CHD8是细胞存活所必需的。尽管采用靶向BCR-ABL的激酶抑制剂进行治疗，该疾病的预后仍然较差。尽管CHD8被认为与自闭症谱系障碍（autism spectrum disorder）的发病风险相关，同时在前列腺癌与肺癌中发挥肿瘤抑制作用，但其发挥功能的具体分子机制仍未阐明，且从未在造血系统恶性肿瘤的研究背景中被探讨过。本研究证实，在B细胞急性淋巴细胞白血病（B-cell acute lymphoblastic leukemia，简称B-ALL）细胞中敲低CHD8会引发细胞死亡。尽管多种B细胞恶性肿瘤的存活依赖于CHD8的表达，但T细胞恶性肿瘤在CHD8敲低后仅表现出轻微的表型变化。此外，在T细胞恶性肿瘤中异位表达Notch1胞内结构域（Notch1 intracellular domain），可部分缓解CHD8表达缺失所带来的有害效应。本研究结果表明，CHD8在细胞存活中发挥的作用具有情境依赖性，抑制CHD8或可成为B淋巴细胞恶性肿瘤的有效治疗手段。