FEV通过粘附分子ICAM-1调控白血病干细胞的功能及其机制研究

Leukemic stem cells (LSCs) is considered to drive chemotherapeutic resistance and relapse. Understanding functional regulation of LSCs especially the difference between normal hematopoietic stem cells (HSCs) and LSCs is crucial to selectively eradicate LSCs. We recently reported that FEV-knockdown markedly impaired the cancer-propagation of LSCs but not affect the function of normal HSCs, illustrating that FEV regulate LSCs function selectively. Recently study showed that ICAM-1 expression level decreased in reconstituted leukemic cells with FEV-Knockdown from recipient mice. Which indicated that FEV may regulate the interaction between LSCs and microenvironment factors by controlling ICAM-1 expression level and finally impact the cancer-propagation capacity of LSCs. In the proposed project, we will use well-established MLL-AF9 acute myeloid leukemia (AML) model, xenograft model, real-time ex vivo tracking imaging and in situ tissue immunofluorescence to study FEV function in LSCs propagation, to determine the role of FEV in the interaction between LSCs and bone marrow microenvironment factors, to explore the mechanism of LSCs regulated by FEV via ICAM-1 signal pathway. And thus the research achievement will propose a theoretical foundation and a new therapeutic approach for leukemia resistance and relapse.

白血病干细胞（LSCs）是引起白血病化疗耐受和复发的主要原因。探讨LSCs的功能调控机理尤其是与造血干细胞（HSCs）调控的差异，对于特异性清除LSCs具有重要的作用。我们前期工作发现干扰转录因子FEV的表达明显降低LSCs在受体小鼠中的白血病重建但不影响正常HSCs的功能，说明FEV特异性调控LSCs的功能。我们最新研究发现干扰FEV表达的白血病细胞中粘附分子ICAM-1的表达显著减少，提示FEV可能通过调控ICAM-1的表达，影响LSCs与微环境的相互作用，从而调控LSCs的肿瘤重建能力。本申请项目拟以MLL-AF9急性髓细胞白血病模型为基础，利用异种移植、离体实时示踪和原位免疫荧光等技术研究FEV对LSCs的作用，探索FEV对LSCs与骨髓微环境成分相互作用的调控，探讨FEV通过ICAM-1信号通路调控LSCs白血病重建的机制。本项目将为白血病的耐药和复发提供理论依据和新的治疗策略。

复发和耐药性是白血病治疗面临的重要难题。寻找特异性靶点或药物是改善临床预后所亟需的。本课题组前期报道转录因子FEV在多数儿童白血病中表达，成人正常造血和白血病中均保持沉默，其表达减少降低白血病干细胞在受体小鼠中的重建。我们在成人白血病中的进一步研究发现FEV在难治复发白血病中重新表达。FEV敲减显著降低白血病小鼠的发病时间，抑制白血病细胞的增殖和归巢。FEV通过直接调控ITGA4的转录，激活整合素信合通路，维持白血病细胞的粘附、迁移和增殖，介导其对白血病细胞的作用。ITGA4的封闭性抗体显著抑制白血病细胞和白血病干细胞的克隆集落形成和归巢能力。总之，FEV通过直接调控ITGA4介导其对难治复发白血病细胞扩增和归巢的作用，靶向ITGA4的治疗抑制难治复发患者白血病细胞的增殖和归巢。本课题的实验结果明确了FEV在难治复发白血病中作用及机制，提示ITGA4的抗体Natalizumab可能在难治复发白血病的治疗中具有潜在的应用价值，为临床治疗策略提供了重要的实验和理论基础。