MYC 作为自然杀伤细胞介导的淋巴恶性肿瘤免疫监视的开关发挥作用。
MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies.
机构信息
Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA.
Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA.
出版信息
Nat Commun. 2020 Jun 5;11(1):2860. doi: 10.1038/s41467-020-16447-7.
The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYC mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYC T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.
MYC 癌基因驱动 T 细胞和 B 细胞淋巴恶性肿瘤，包括伯基特淋巴瘤（BL）和急性淋巴细胞白血病（ALL）。在这里，我们发现在携带 MYC 驱动的 T 细胞淋巴瘤的 SRα-tTA/Tet-O-MYC 小鼠中，自然杀伤（NK）细胞数量出现系统性减少。MYC T 细胞淋巴瘤小鼠脾脏中残留的 mNK 细胞表现出 NK 效应细胞终末分化途径的紊乱。淋巴瘤内在的 MYC 通过转录抑制 STAT1/2 和 I 型干扰素（IFNs）的分泌来阻断 NK 成熟。用 I 型 IFN 治疗携带 T 细胞淋巴瘤的小鼠可以通过挽救 NK 细胞成熟来提高存活率。成熟 NK 细胞的过继转移足以延迟 MYC 失活后 T 细胞淋巴瘤的生长和复发。在 MYC 驱动的 BL 患者中，STAT1 和 STAT2 的低表达与活化的 NK 细胞缺失显著相关，并预示着不良的临床结局。因此，我们的研究为未来开发基于 NK 细胞的疗法有效治疗 MYC 驱动的淋巴瘤提供了依据。
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