Runx1功能缺失突变导致eIF4E选择性翻译Bcl-2及其在AML化疗耐受中的分子机制研究

Runx1功能缺失突变是急性髓系白血病（acute myeloid leukemia,AML）的一个独立预后指标，携带该突变的患者对化疗不敏感。化疗药物诱导细胞凋亡的过程主要依赖Bcl-2家族蛋白的调控,通常AML化疗耐受患者伴有Bcl-2的高表达。前期在小鼠模型和临床AML样品实验中，我们发现Runx1功能缺失细胞中抑制Bcl-2的表达能显著增加其对p53诱导的细胞凋亡的敏感性。这提示Runx1功能缺失突变通过调控Bcl-2促进细胞化疗耐受，但其分子机制尚不明确。我们推测，应激条件下Runx1功能缺失突变导致细胞通过eIF4E选择性翻译Bcl-2，从而逃逸凋亡产生化疗耐受。本课题拟以Runx1条件性敲除小鼠和人脐带血干细胞为研究模型，阐明Runx1功能缺失突变导致Bcl-2选择性翻译的分子机制，并将在动物模型和临床样本中验证相关机制。研究结果有望为相关恶性肿瘤的临床治疗提供新依据。

In acute myeloid leukemia (AML) treatment, Runx1 loss of function (LOF) mutation was found to be an independent prognostic factor and patients carrying this mutation were insensitive to chemotherapy. Apoptosis of tumor cells caused by chemotherapy drugs mainly depends on the regulation of Bcl-2 family proteins and high expression of Bcl-2 is usually correlated with chemo-resistance in AML patients. In our previous study using mouse models and human clinical AML samples both in vitro and in vivo, we found that Bcl-2 inhibition could significantly increase the sensitivity of cells with Runx1 LOF mutation to p53 induced apoptosis. This suggests that Bcl-2 regulates chemo-resistance in cells with Runx1 LOF mutation, yet the molecular mechanism has not been revealed. We believe that upon stress Runx1 LOF mutation cells would selectively translate Bcl-2 protein, thereby escape from apoptosis and eventually demonstrate with chemo-resistance. In this study, mouse and human hematopoietic stem cells carrying Runx1 LOF mutation will be utilized as models and the molecular mechanism of eIF4E-mediated Bcl-2 selective translation will be explored. Both mouse AML models and in-vitro test of clinic samples will be used for validation. The data of this study will provide research evidence for Runx1 LOF mutation-related cancer treatment.