NFAT transcriptome in T-ALL

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with few available targeted therapies. We previously reported that the phosphatase calcineurin (Cn) is required for LIC (leukemia Initiating Capacity) potential of T-ALL pointing to Cn as an interesting therapeutic target. Calcineurin inhibitors have however unwanted side effects. NFAT transcription factors play crucial roles downstream of calcineurin during thymocyte development, T cell differentiation, activation and energy. Here we elucidate NFAT functional relevance in T-ALL. Using murine T-ALL models in which Nfat genes can be inactivated either singly or in combination, we show that NFATs are required for T-ALL LIC potential and essential to survival, proliferation and migration of T-ALL cells. We also demonstrate that Nfat genes are functionally redundant in T-ALL and identified a node of genes commonly deregulated upon Cn or NFAT inactivation, which may serve as future candidate targets for T-ALL.T细胞急性淋巴细胞白血病（T-cell acute lymphoblastic leukemia, T-ALL）是一种侵袭性恶性肿瘤，可用靶向治疗手段极少。本团队此前曾报道，磷酸酶钙调神经磷酸酶（calcineurin, Cn）是T-ALL白血病起始细胞能力（leukemia Initiating Capacity, LIC）维持所必需的因子，提示Cn可作为极具潜力的治疗靶点。然而钙调神经磷酸酶抑制剂存在不良副作用。活化T细胞核因子（Nuclear Factor of Activated T cells, NFAT）转录因子在钙调神经磷酸酶下游的胸腺细胞发育、T细胞分化、活化及能量代谢过程中发挥关键作用。本研究阐明了NFAT在T-ALL中的功能相关性。我们采用可单基因或联合敲除Nfat基因的小鼠T-ALL模型开展实验，结果显示NFAT是T-ALL白血病起始细胞能力维持所必需的因子，且对T-ALL细胞的存活、增殖与迁移至关重要。本研究同时证实，Nfat基因在T-ALL中存在功能冗余性，并鉴定出一组在Cn或NFAT失活后共同失调的基因节点，该节点有望成为T-ALL未来的潜在治疗靶点。