HMGB1在髓系分化和急性髓系白血病中的功能机制研究

As a multi-functional protein, HMGB1 has been reported to regulate many physiological and pathological processes, and its abnormal expression is strongly associated with pathogenesis of many disorders. However, the role and mechanism of HMGB1 in myeloid differentiation and acute myeloid leukemia (AML) remain to be determined. Our previous work found that HMGB1 presented high expression in AML patients and displayed gradual decrease during myeloid differentiation. Knock-down of HMGB1 in leukemia cell lines inhibited cell proliferation, increased cell apoptosis and promoted PMA and ATRA-induced myeloid differentiation. This project is further to investigate the regulatory role of HMGB1 in myeloid differentiation and leukemogenesis using CD34+ hematopoietc stem/progenitor cells and leukemia mouse model, and reveal the underlying mechanism from the perspective of HMGB1 as an RNA binding protein, DNA binding protein and its upstream regulation. HMGB1 can also be secreted outside the cell, which would help us analyze the correlation of plasma HMGB1 expression with the clinical characteristics of AML patients. This work will further enrich the existed regulatory network of hematopoiesis and provide novel targets for the clinical diagnosis and therapy of AML patients.

HMGB1作为一个细胞内外均表达的多功能蛋白，参与调控众多生理病理过程，与许多疾病的发生发展密切相关，而其在造血髓系分化和急性髓系白血病中的功能机制尚不明确。我们前期研究发现，HMGB1在急性髓系白血病病例中高表达，而在髓系分化中表达下调。在白血病细胞系中敲低HMGB1的表达显著抑制了细胞增殖，促进了细胞凋亡以及PMA和ATRA诱导的髓系分化过程。在此基础上，本项目将进一步在CD34+造血干/祖细胞和白血病小鼠模型中确定HMGB1在髓系分化和急性髓系白血病中的调控作用，并从其作为RNA结合蛋白、DNA结合蛋白以及自身表达调控等方面揭示其参与髓系分化和急性髓系白血病发生发展的分子机制。另外，我们将结合HMGB1可分泌到细胞外表达的特点，分析其血浆表达与AML临床诊断和治疗预后的相关性。本研究工作将进一步丰富和完善现有的造血调控网络，为AML的临床诊断和治疗提供新的靶点。

鉴定髓系分化以及急性髓系白血病（AML）发生发展中新的关键调控分子，为AML提供明确而强有效的治疗靶点，具有重要的理论和实际意义。HMGB1作为一个细胞内外均表达的多功能蛋白，参与调控众多生理病理过程，与许多疾病的发生发展密切相关，包括白血病。我们的研究发现：（1）HMGB1在AML患者骨髓来源的单个核细胞中显著高表达；（2）HMGB1可以通过促进细胞增殖、抑制细胞凋亡和诱导髓系分化受阻参与AML疾病进展，可以作为一个非常理想的AML治疗靶点；（3）TGFBI作为HMGB1下游的一个靶基因参与调控髓系分化过程；（4）组蛋白去乙酰化酶抑制剂类小分子药物西达本胺可以在AML中显著下调HMGB1的表达，同时抑制AML细胞增殖、促进细胞凋亡和诱导AML细胞分化，可用于AML治疗。该研究为HMGB1作为AML治疗靶点提供了进一步的实验证据，也为西达本胺用于AML临床治疗奠定了理论和实验基础。