Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function

Steven D. Scoville, Ansel P. Nalin, Luxi Chen, Li Chen, Michael H. Zhang, Kathleen McConnell, Susana Beceiro Casas, Gabrielle Ernst, Abd Al-Rahman Traboulsi, Naima Hashi, Monica Williams, Xiaoli Zhang, Tiffany Hughes, Anjali Mishra, Don M. Benson, Jennifer N. Saultz, Jianhua Yu, Aharon G. Freud, Michael A. Caligiuri and Bethany L. Mundy-Bosse

Key Points

  • Human and murine AML activate the AHR pathway, which can regulate miR-29b expression and impair NK cell development and function.

  • AML-induced impairment of NK cell development and function can be reversed with AHR antagonist.

Publisher's Note: There is a Blood Commentary on this article in this issue.


Acute myeloid leukemia (AML) can evade the mouse and human innate immune system by suppressing natural killer (NK) cell development and NK cell function. This is driven in part by the overexpression of microRNA (miR)–29b in the NK cells of AML patients, but how this occurs is unknown. In the current study, we demonstrate that the transcription factor aryl hydrocarbon receptor (AHR) directly regulates miR-29b expression. We show that human AML blasts activate the AHR pathway and induce miR-29b expression in NK cells, thereby impairing NK cell maturation and NK cell function, which can be reversed by treating NK cells with an AHR antagonist. Finally, we show that inhibition of constitutive AHR activation in AML blasts lowers their threshold for apoptosis and decreases their resistance to NK cell cytotoxicity. Together, these results identify the AHR pathway as a molecular mechanism by which AML impairs NK cell development and function. The results lay the groundwork in establishing AHR antagonists as potential therapeutic agents for clinical development in the treatment of AML.

  • Submitted March 7, 2018.
  • Accepted August 22, 2018.
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