MALAT1通过抑制p53活性促进AML恶性进展的分子机制

Acute myeloid leukemia (AML) is the most common form of leukemia in adults and has a poor prognosis. It is established that inactivation of p53 is a key driver of AML. Our recent work has demonstrated that long noncoding RNA (lncRNA) is closely related to the activity of p53 (Leukemia, 2017), but the underlying mechanisms are waiting to be explored. Our preliminary data showed that the expression of lncRNA MALAT1 that was inversely related to p53 content was significantly increased, and it could promote tumor growth in AML. It is known that p53 mutation rarely occurs in AML. MDM2 exerts an important role in inversely regulating on the p53 activity. Furthermore, we found that MALAT1 bound to p53 protein and it promoted the binding between p53 and MDM2; MALAT1 also promoted MDM2 expression while mTOR, another key regulator of AML, was activated. Therefore, we speculate that MALAT1 promotes the binding of MDM2 to p53 by its own capacity of p53 binding; meanwhile, MALAT1 promotes MDM2 expression through mTOR activation, resulting in a decrease of p53 expression to promote tumor growth. Clearly, this hypothesis needs to be demonstrated by further analysis in cell models, animals in vivo and clinical samples. If the project is successful, it is very probable to provide a new target for therapeutic improvement of AML treatment.

急性髓系白血病(AML)是成人最常见的白血病，预后差。p53失活是AML的关键驱动因素。我们的研究显示长链非编码RNA (lncRNA)与p53活性密切相关 (Leukemia, 2017)，但机制尚需探索。前期工作发现AML中lncRNA MALAT1的表达显著增加,并与p53含量呈明显负相关，且其能促进肿瘤生长。AML中p53很少突变，MDM2对其活性发挥了重要的负向调控作用。我们发现MALAT1能与p53蛋白结合，并能增加p53与MDM2之间的结合；MALAT1还可促进MDM2的表达，同时还能激活AML另一关键调控分子mTOR。我们推测MALAT1一方面通过与p53结合促进MDM2与p53的结合；一方面通过mTOR促进MDM2的表达，从而使p53表达下降、促进肿瘤生长。该推测还将通过细胞学实验、模式动物和临床样本进一步论证。如果本课题得以成功，将可能为提高AML疗效提供新靶点。

白血病是造血系统最常见的恶性肿瘤，其中急性髓细胞白血病（Acute myeloid leukemia, AML）是最常见的白血病类型。现阶段耐药、难治复发等临床问题仍是AML治疗面临的主要挑战，因此，发现新的治疗靶点迫在眉睫。AML的研究在过去几十年主要集中在蛋白编码基因上，虽然这些蛋白编码基因对于探索AML遗传学改变和筛选生物靶标有极大的帮助，但AML耐药、难治复发等临床问题仍未能完全解决。长链非编码RNA（Long non-coding RNA，lncRNA）通过参与基因转录和翻译，调控肿瘤细胞多种生物学行为。目前在AML中，lncRNA相关的研究仍然有限，在临床转化应用中仍处于起步阶段。本研究通过AML临床样本测序筛选出差异表达的lncRNA MALAT1。扩大临床样本检测证实其在AML患者中显著高表达并与预后负相关。我们进一步发现MALAT1在AML中促进AML细胞增殖、抑制凋亡发挥促癌作用。对敲除MALAT1的细胞做RNAseq和蛋白质谱（Mass spectrometry, MS）分析发现MALAT1影响DNA损伤和修复。体外实验研究证实MALAT1能够抑制DNA损伤。深入分子机制研究，我们发现MALAT1与DNA损伤修复的关键分子ATM结合，影响AML细胞对DNA损伤抵抗，最终促进AML恶性进展。基于以上研究结果，我们认为MALAT1通过与ATM结合调控DNA损伤修复，进而促进AML恶性进展。本研究为深入了解AML发生发展机制以及探索AML新治疗靶点的提供理论依据。