骨髓微环境中IGFBP2参与调控急性T淋巴细胞白血病耐药的机制研究

T cell acute lymphoblastic leukemia (T-ALL) is characterized by a clonal expansion of immature T-cell progenitors that do not retain the capacity to differentiate normally to mature blood cells. How to prevent drug resistance is the heat point of T-ALL investigation. In vivo both of the hypoxia and bone marrow stromal cells (BMSC) are responsible for the drug resistance mediated by the bone marrow microenviorment. We found an elevated IGFBP2 expression in T-ALL cocultured with BMSC and an even higher IGFBP2 expression when T-ALL cocultured with BMSC in hypoxia. Serum IGFBP-2 was identified as an independent factor that adds additional information for the prediction of events (relapse or treatment failure) to the conventional prognostic factors such as white blood cell count and platelet count at diagnosis. All above hints that IGFBP2 may participate in drug resistance of T-ALL regulated by both of the BMSC and hypoxia. To mimic in vivo bone marrow microenviorment, we coculture T-ALL cells with BMSC in hypoxia, research for the impaction of bone marrow microenviorment in drug resistance, identify the regulation of bone marrow microenviorment to IGFBP2, further expolore the mechanisms of IGFBP2 in drug resistance of T-ALL. We will also investigate possibility of preventing drug resistance through experimentation in vivo. The accomplishment of our investigation will establish a theoretical basis for prevention of drug resistance and eradication of minimal residual disease in T-ALL.

急性T淋巴细胞白血病（T-ALL）是严重威胁人类健康的造血系统恶性疾患，细胞耐药性产生是T-ALL难治、复发的主要原因之一。体内骨髓微环境的乏氧状态与骨髓基质细胞（BMSC）共同介导了白血病耐药。我们前期研究发现T-ALL细胞与BMSC共培养后IGFBP2表达升高，乏氧环境下共培养的T-ALL细胞IGFBP2表达显著高于常氧对照。血清IGFBP2是预测ALL复发的独立危险因子，其水平升高与疾病预后不良相关。因此我们推测IGFBP2参与调控BMSC与乏氧环境共同介导的白血病耐药。本课题拟利用T-ALL细胞与BMSC在乏氧环境下共培养模拟体内骨髓微环境，研究骨髓微环境对T-ALL细胞药物敏感性的影响，明确IGFBP2参与调控骨髓微环境介导的T-ALL细胞耐药的作用机制，探讨靶向IGFBP2逆转 T-ALL复发耐药的可行性。预期目标的实现对于克服T-ALL细胞耐药、清除微小残留病变具有重要意义。

急性T淋巴细胞白血病（T-ALL）是严重威胁人类健康的造血系统恶性疾患，细胞耐药性产生是T-ALL难治、复发的主要原因之一。体内骨髓微环境的乏氧状态与骨髓基质细胞（BMSC）共同介导了白血病耐药。我们研究发现T-ALL细胞与BMSC共培养后IGFBP2表达升高，乏氧环境下共培养的T-ALL细胞IGFBP2表达显著高于常氧对照。血清IGFBP2是预测ALL复发的独立危险因子，其水平升高与疾病预后不良相关。本课题利用T-ALL细胞与BMSC在乏氧环境下共培养模拟体内骨髓微环境，发现IGFBP2参与调控骨髓微环境介导的T-ALL细胞耐药，靶向IGFBP2可逆转 T-ALL复发耐药。同时，在实体瘤中研究发现COX-2/PGE2轴在乏氧状态下可调控肝癌细胞HIF-2α的表达及活性，进而促进肿瘤进展。本课题的顺利完成可为T-ALL及肝癌的靶向治疗提供理论依据。