STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation

Jiaying Xie; Mengyao Sheng; Shaoqin Rong; Dan Zhou; Chao Wang; Wanling Wu; Jingru Huang; Yue Sun; Yuanxian Wang; Pingyue Chen; Yushuang Wu; Yuanxian Wang; Lan Wang; Bo O Zhou; Xinxin Huang; Colum P Walsh; Stefan K Bohlander; Jian Huang; Xiaoqin Wang; Guo-Liang Xu; Hai Gao; Yuheng Shi

doi:10.1038/s41375-023-02055-z

STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation

Jiaying Xie, Mengyao Sheng, Shaoqin Rong, Dan Zhou, Chao Wang, Wanling Wu, Jingru Huang, Yue Sun, Yuanxian Wang, Pingyue Chen, Yushuang Wu, Yuanxian Wang, Lan Wang, Bo O Zhou, Xinxin Huang, Colum P Walsh, Stefan K Bohlander, Jian Huang, Xiaoqin Wang, Guo-Liang XuHai Gao, Yuheng Shi

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Abstract

Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases. [Abstract copyright: © 2023. The Author(s).]

Original language	English
Pages (from-to)	2457-2467
Number of pages	11
Journal	Leukemia
Volume	37
Issue number	12
Early online date	10 Oct 2023
DOIs	https://doi.org/10.1038/s41375-023-02055-z
Publication status	Published online - 10 Oct 2023

Bibliographical note

Funding Information:
We acknowledge L. Wang, R. Ren, J. Chen, and Q. Wang for the discussions; J. Wang, H. Zhang, T. Gu, J. Chen, and R. Su for critical reading of the manuscript; T. Chen, X. Huang and X. Wang for providing BM cells of mouse AML model, human cord blood and AML patient samples; Z. Lu for providing Sting mice; X. Liu for providing B6.SJL mice. SKB is supported by Leukemia & Blood Cancer New Zealand and the family of Marijana Kumerich. This work was supported by the National Key R&D Program of China (Grant No. 2021YFA1102200 and No. 2022YFA1303000 to YS), the National Natural Science Foundation of China (32000420 to DZ; 31901011 and 82270163 to YS), the Shanghai Sailing Program (18YF1412200), the Natural Science Foundation of Shanghai (20ZR1408000), the Fudan University Start-up Research Grant (IDH1340038, IDH1340045, IDH1340046, IDH1340059), the Medical Science Data Center in Shanghai Medical College of Fudan University. −/−

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© 2023, The Author(s).

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s41375-023-02055-zFinal published version, 4.15 MBLicence: CC BY

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Xie, J., Sheng, M., Rong, S., Zhou, D., Wang, C., Wu, W., Huang, J., Sun, Y., Wang, Y., Chen, P., Wu, Y., Wang, Y., Wang, L., Zhou, B. O., Huang, X., Walsh, C. P., Bohlander, S. K., Huang, J., Wang, X., ... Shi, Y. (2023). STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation. Leukemia, 37(12), 2457-2467. Advance online publication. https://doi.org/10.1038/s41375-023-02055-z

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title = "STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation",

abstract = "Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases. [Abstract copyright: {\textcopyright} 2023. The Author(s).]",

author = "Jiaying Xie and Mengyao Sheng and Shaoqin Rong and Dan Zhou and Chao Wang and Wanling Wu and Jingru Huang and Yue Sun and Yuanxian Wang and Pingyue Chen and Yushuang Wu and Yuanxian Wang and Lan Wang and Zhou, {Bo O} and Xinxin Huang and Walsh, {Colum P} and Bohlander, {Stefan K} and Jian Huang and Xiaoqin Wang and Guo-Liang Xu and Hai Gao and Yuheng Shi",

note = "Funding Information: We acknowledge L. Wang, R. Ren, J. Chen, and Q. Wang for the discussions; J. Wang, H. Zhang, T. Gu, J. Chen, and R. Su for critical reading of the manuscript; T. Chen, X. Huang and X. Wang for providing BM cells of mouse AML model, human cord blood and AML patient samples; Z. Lu for providing Sting mice; X. Liu for providing B6.SJL mice. SKB is supported by Leukemia & Blood Cancer New Zealand and the family of Marijana Kumerich. This work was supported by the National Key R&D Program of China (Grant No. 2021YFA1102200 and No. 2022YFA1303000 to YS), the National Natural Science Foundation of China (32000420 to DZ; 31901011 and 82270163 to YS), the Shanghai Sailing Program (18YF1412200), the Natural Science Foundation of Shanghai (20ZR1408000), the Fudan University Start-up Research Grant (IDH1340038, IDH1340045, IDH1340046, IDH1340059), the Medical Science Data Center in Shanghai Medical College of Fudan University. −/− Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = oct,

day = "10",

doi = "10.1038/s41375-023-02055-z",

language = "English",

volume = "37",

pages = "2457--2467",

journal = "Leukemia",

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Xie, J, Sheng, M, Rong, S, Zhou, D, Wang, C, Wu, W, Huang, J, Sun, Y, Wang, Y, Chen, P, Wu, Y, Wang, Y, Wang, L, Zhou, BO, Huang, X, Walsh, CP, Bohlander, SK, Huang, J, Wang, X, Xu, G-L, Gao, H & Shi, Y 2023, 'STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation', Leukemia, vol. 37, no. 12, pp. 2457-2467. https://doi.org/10.1038/s41375-023-02055-z

TY - JOUR

T1 - STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation

AU - Xie, Jiaying

AU - Sheng, Mengyao

AU - Rong, Shaoqin

AU - Zhou, Dan

AU - Wang, Chao

AU - Wu, Wanling

AU - Huang, Jingru

AU - Sun, Yue

AU - Wang, Yuanxian

AU - Chen, Pingyue

AU - Wu, Yushuang

AU - Wang, Yuanxian

AU - Wang, Lan

AU - Zhou, Bo O

AU - Huang, Xinxin

AU - Walsh, Colum P

AU - Bohlander, Stefan K

AU - Huang, Jian

AU - Wang, Xiaoqin

AU - Xu, Guo-Liang

AU - Gao, Hai

AU - Shi, Yuheng

N1 - Funding Information: We acknowledge L. Wang, R. Ren, J. Chen, and Q. Wang for the discussions; J. Wang, H. Zhang, T. Gu, J. Chen, and R. Su for critical reading of the manuscript; T. Chen, X. Huang and X. Wang for providing BM cells of mouse AML model, human cord blood and AML patient samples; Z. Lu for providing Sting mice; X. Liu for providing B6.SJL mice. SKB is supported by Leukemia & Blood Cancer New Zealand and the family of Marijana Kumerich. This work was supported by the National Key R&D Program of China (Grant No. 2021YFA1102200 and No. 2022YFA1303000 to YS), the National Natural Science Foundation of China (32000420 to DZ; 31901011 and 82270163 to YS), the Shanghai Sailing Program (18YF1412200), the Natural Science Foundation of Shanghai (20ZR1408000), the Fudan University Start-up Research Grant (IDH1340038, IDH1340045, IDH1340046, IDH1340059), the Medical Science Data Center in Shanghai Medical College of Fudan University. −/− Publisher Copyright: © 2023, The Author(s).

PY - 2023/10/10

Y1 - 2023/10/10

N2 - Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases. [Abstract copyright: © 2023. The Author(s).]

AB - Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases. [Abstract copyright: © 2023. The Author(s).]

UR - http://www.scopus.com/inward/record.url?scp=85173677837&partnerID=8YFLogxK

U2 - 10.1038/s41375-023-02055-z

DO - 10.1038/s41375-023-02055-z

M3 - Article

C2 - 37816954

SN - 1476-5551

VL - 37

SP - 2457

EP - 2467

JO - Leukemia

JF - Leukemia

IS - 12

ER -

STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation

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