Ph＋急性淋巴细胞白血病（Ph＋ALL）疗效差，微小残留病和耐药是其难以治愈主要原因。申请者在既往自然基金研究中发现：CX43缺失导致骨髓基质GJIC功能降低有助于急性淋巴细胞白血病的残留耐药，但CX43缺失的具体原因不清楚。前期研究证明：Ph+ALL通过衍生miR-93微泡发挥阻抑骨髓基质GJIC功能的作用但其胞内通路不明，推测其可能通过EphA4下调E-cadherin表达而实现对CX43膜定位的干扰，从而达到阻抑骨髓基质GJIC功能作用，继而有助于Ph＋ALL残留耐药作用。本研究应用基因芯片结合生物信息学、基因组学、表型验证、动物实验等方法从一新的角度探讨Ph＋ALL细胞对白血病造血微环境的“改造”作用及机制，从白血病与造血微环境“crosstalk”这一新的角度去探索白血病细胞的残留耐药机制，寻求清除残留白血病的新方法。

Minimal residual disease (MRD) and drug resistance were main causes for the poor outcome of Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ALL). In previous Natural Science Foundation study, we found that the low expression of CX43 on the surface of bone marrow stromal cells in patients with ALL results in the dysfunction of gap junction intercellular communication (GJIC), which contributed to MRD and drug resistance. But the reason of decreased expression of CX43 remains unclear. Our previous studies found that miR-93 exosome derived from Ph＋ALL cells could restrain the function of GJIC of bone marrow stromal cells, but its intracellular signal pathway remains unclear. We speculate that the target gene EphA4 disturb membrane localization of CX43 and suppress the function of GJIC by downregulating the expression of E-cadherin . In this study, microarray bioinformatics, molecular biology, phenotypic validation,animal experiments and other methods will be used to investigate the effect and mechanism of Ph＋ALL cells for the reform of hematopoietic microenvironment. We explore the mechanism of residual disease and drug resistance from the perspective of the "crosstalk " between leukemia cells and hematopoietic microenvironment, and seek a new method to completely eliminate residual leukemic cells.