白血病是儿童常见的恶性肿瘤。耐药是难治、复发的重要因素，自噬在其中发挥重要作用。但自噬起始时HMGB1从胞核转位到胞浆，和关键蛋白复合物ULK1-FIP200、Beclin1-HMGB1，三者之间的调控机制尚不明确。前期研究和预实验发现ULK1-FIP200通过协助HMGB1转位促进Beclin1-HMGB1形成，这一过程与HMGB1乙酰化有关；利用生物信息学还预测了STAT5可能激活SIRT6转录活化并通过PARP-1影响HMGB1的乙酰化。因此我们推测ULK1-FIP200是通过磷酸化激活STAT5，并导致SIRT6转录活化，借助PARP-1对HMGB1进行乙酰化修饰来协助其转位，从而促进下游Beclin1-HMGB1组装，介导自噬相关白血病细胞耐药。本项目拟通过体内外实验，明确这一科学假说，对深入阐明自噬介导的白血病耐药机制有重要意义，有望为解决白血病乃至其他肿瘤耐药难题提供新思路。

Acute lymphoblastic leukaemia is a common paediatric cancer. The acquisition of drug resistance is a significant obstacle to the achievement of favourable outcomes, and autophagy is regarded as a mechanism that underlies chemoresistance. As critical effector of autophagosome formation, the Ulk13-FIP200 complex and the Beclin1-HMGB1 complex are not independent modules. In addition, the translocation of HMGB1 from nucleus to cytoplasm is a crucial molecular event during autophagy. However, the association between the activities of these complexes and the function of HMGB1 translocation, specifically in leukaemia, have yet to be clearly elucidated. Our previous studies and preliminary experiments show that Ulk1-FIP200 complex functions upstream of the Beclin1-HMGB1 and HMGB1 translocation is involved in their regulatory relationships. The acetylation of HMGB1 is related to its translocation. Bioinformatics prediction shows that STAT5 may activate SIRT6 by stimulating the transcription initiation and then influence the acetylation of HMGB1 via PARP-1. Therefore we assume that the ULK1-FIP200 phosphorylates STAT5, activates SIRT6 and assists the HMGB1 translocation by acetylating HMGB1 via PARP-1, and consequently promotes the assembly of the Beclin1-HMGB1 and promotes autophagy-related chemoresistance in leukaemia. We intend to prove this science hypothesis using in vitro and in vivo methods. The findings will have important implications for further study on the mechanism of autophagy-related chemoresistance. We are likely to develop new combination therapy strategies, render tumour cells more susceptible to conventional therapies and overcome drug resistance in leukaemia, and even other tumours.