非经典Wnt信号在骨髓微环境诱导耐药中的作用及机制研究

白血病细胞耐药是影响白血病患者长期生存和预后的主要因素之一，其直接表现为白血病细胞残留的增多和对化疗不敏感。白血病细胞处于相对静止状态是对化疗耐药的重要机制之一。Flamingo（Fmi）和Frizzled-8（Fz8）是非经典Wnt信号通路成员，在调节造血干细胞处于相对静止状态中发挥关键性作用。然而，我们发现Fmi在对化疗不敏感患者中表达明显升高，暗示其可能与白血病耐药有关。为此，本研究中通过上调或下调Fmi和Fz8在白血病细胞株的表达，与OP9细胞共培养，观察Fmi与Fz8的相互作用、对白血病细胞生物学性状、化疗敏感性的影响以及经典Wnt信号的变化，并探讨其中的机制。同时以修饰的白血病细胞建立小鼠白血病模型，分别观察白血病细胞归巢能力、造血微环境中定位、细胞周期等变化及白血病细胞对化疗的敏感性的变化。从而深入理解非经典Wnt信号在骨髓微环境诱导耐药中发挥的作用。

Resistance is one of the main factors to affect the long-term survival and cure of patients with leukemia, and its performance directly increased minimal residual disease and therapeutic resistance. Quiescence of Leukemia cells is one of the important mechanisms of resistance to chemotherapy. Flamingo (Fmi) and Frizzled (Fz) 8,members of noncanonical Wnt signaling, plays a critical role in maintenance of quiescent HSCs. we found, however, that Fmi in relapsed and refractory patients with leukemia express significantly higher, suggesting that it may be associated with drug resistance. Therefore, upregulated or downregulated Fmi and Fz8 expressed leukemia cells co-cultured with OP9, observing the biological characteristics and sensitivity to chemotherapy in leukemia cells, exploring the potential mechanisms. To establish a mouse model of leukemia with upregulated or downregulated Fmi and Fz8 expressed in leukemia cell, observing the ability of leukemia cells homing to the hematopoietic microenvironment, cell cycle, chemotherapy sensitivity and minimal residual disease, so as to explore the role of non-canonical Wnt signaling in the hematopoietic microenvironment-mediated resistance.