NK cells are known to be developmentally blocked and functionally inhibited in patients with acute myeloid leukemia (AML), resulting in poor clinical outcomes. In this study, we demonstrate that whereas NK cells are inhibited, closely related type 1 innate lymphoid cells (ILC1s) are enriched in the bone marrow of leukemic mice and in patients with AML. Because NK cells and ILC1s share a common precursor (ILCP), we asked if AML acts on the ILCP to alter developmental potential. A combination of ex vivo and in vivo studies revealed that AML skewing of the ILCP toward ILC1s and away from NK cells represented a major mechanism of ILC1 generation. This process was driven by AML-mediated activation of the aryl hydrocarbon receptor (AHR), a key transcription factor in ILCs, as inhibition of AHR led to decreased numbers of ILC1s and increased NK cells in the presence of AML. These results demonstrate a mechanism of ILC developmental skewing in AML and support further preclinical study of AHR inhibition in restoring normal NK cell development and function in the setting of AML.

众所周知，急性髓系白血病 (AML) 患者的 NK 细胞发育受阻且功能受到抑制，导致临床结果不佳。在这项研究中，我们证明，尽管 NK 细胞受到抑制，但密切相关的 1 型先天淋巴细胞 (ILC1) 在白血病小鼠和 AML 患者的骨髓中却富集。由于 NK 细胞和 ILC1 具有共同的前体细胞 (ILCP)，因此我们询问 AML 是否会作用于 ILCP 来改变发育潜力。离体和体内研究相结合表明，AML 使 ILCP 偏向 ILC1 而远离 NK 细胞，这是 ILC1 生成的主要机制。这一过程是由 AML 介导的芳烃受体 (AHR) 激活驱动的，AHR 是 ILC 中的关键转录因子，因为在 AML 存在的情况下，抑制 AHR 会导致 ILC1 数量减少并增加 NK 细胞数量。这些结果证明了 AML 中 ILC 发育倾斜的机制，并支持进一步的临床前研究，即抑制 AHR 来恢复 AML 中 NK 细胞的正常发育和功能。