TY - JOUR
T1 - BATF is a major driver of NK cell epigenetic reprogramming and dysfunction in AML
AU - Kumar, Bijender
AU - Singh, Anand
AU - Basar, Rafet
AU - Uprety, Nadima
AU - Li, Ye
AU - Fan, Huihui
AU - Cortes, Ana Karen Nunez
AU - Kaplan, Mecit
AU - Acharya, Sunil
AU - Shaim, Hila
AU - Xu, Anna C.
AU - Wu, Manrong
AU - Ensley, Emily
AU - Fang, Dexing
AU - Banerjee, Pinaki P.
AU - Garcia, Luciana Melo
AU - Tiberti, Silvia
AU - Lin, Paul
AU - Rafei, Hind
AU - Munir, Maliha Nuzhat
AU - Moore, Madison
AU - Shanley, Mayra
AU - Mendt, Mayela
AU - Kerbauy, Lucila N.
AU - Liu, Bin
AU - Biederstädt, Alexander
AU - Gokdemir, Elif
AU - Ghosh, Susmita
AU - Kundu, Kiran
AU - Reyes-Silva, Francia
AU - Jiang, Xin Ru
AU - Wan, Xinhai
AU - Gilbert, April L.
AU - Dede, Merve
AU - Mohanty, Vakul
AU - Dou, Jinzhuang
AU - Zhang, Patrick
AU - Liu, Enli
AU - Muniz-Feliciano, Luis
AU - Deyter, Gary M.
AU - Jain, Abhinav K.
AU - Rodriguez-Sevilla, Juan Jose
AU - Colla, Simona
AU - Garcia-Manero, Guillermo
AU - Shpall, Elizabeth J.
AU - Chen, Ken
AU - Abbas, Hussein A.
AU - Rai, Kunal
AU - Rezvani, Katayoun
AU - Daher, May
N1 - Publisher Copyright:
© 2024 The Authors.
PY - 2024/9/11
Y1 - 2024/9/11
N2 - Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT, and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.
AB - Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT, and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.
UR - http://www.scopus.com/inward/record.url?scp=85204101164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85204101164&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adp0004
DO - 10.1126/scitranslmed.adp0004
M3 - Article
C2 - 39259809
AN - SCOPUS:85204101164
SN - 1946-6234
VL - 16
JO - Science translational medicine
JF - Science translational medicine
IS - 764
M1 - eadp0004
ER -