TY - JOUR
T1 - Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function
AU - Scoville, Steven D.
AU - Nalin, Ansel P.
AU - Chen, Luxi
AU - Chen, Li
AU - Zhang, Michael H.
AU - McConnell, Kathleen
AU - Casas, Susana Beceiro
AU - Ernst, Gabrielle
AU - Al-Rahman Traboulsi, Abd
AU - Hashi, Naima
AU - Williams, Monica
AU - Zhang, Xiaoli
AU - Hughes, Tiffany
AU - Mishra, Anjali
AU - Benson, Don M.
AU - Saultz, Jennifer N.
AU - Yu, Jianhua
AU - Freud, Aharon G.
AU - Caligiuri, Michael A.
AU - Mundy-Bosse, Bethany L.
N1 - Funding Information:
This work was supported by an American Association for Cancer Research award (17-20-46-MUND) (B.L.M.-B.) and by National Cancer Institute, National Institutes of Health grants (CA89341, CA095426, CA163205, CA016058, and CA068458 [M.A.C.] and F30CA196244 [S.D.S.]). The authors also gratefully acknowledge the use of the Ohio State University Comprehensive Cancer Center Analytical Cytometry Shared Resource and the AML cells provided by the Ohio State University Comprehensive Cancer Center Leukemia Tissue Bank Shared Resource, which is supported by National Cancer Institute, National Institutes of Health (P30CA016058).
Publisher Copyright:
© 2018 by The American Society of Hematology.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/10/25
Y1 - 2018/10/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055617608&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055617608&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-03-838474
DO - 10.1182/blood-2018-03-838474
M3 - Article
C2 - 30158248
AN - SCOPUS:85055617608
VL - 132
SP - 1792
EP - 1804
JO - Blood
JF - Blood
SN - 0006-4971
IS - 17
ER -