ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Jie Li; Phillip M. Galbo; Weida Gong; Aaron J. Storey; Yi Hsuan Tsai; Xufen Yu; Jeong Hyun Ahn; Yiran Guo; Samuel G. Mackintosh; Ricky D. Edmondson; Stephanie D. Byrum; Jason E. Farrar; Shenghui He; Ling Cai; Jian Jin; Alan J. Tackett; Deyou Zheng; Gang Greg Wang

doi:10.1038/s41467-021-21357-3

ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Jie Li, Phillip M. Galbo, Weida Gong, Aaron J. Storey, Yi Hsuan Tsai, Xufen Yu, Jeong Hyun Ahn, Yiran Guo, Samuel G. Mackintosh, Ricky D. Edmondson, Stephanie D. Byrum, Jason E. Farrar, Shenghui He, Ling Cai, Jian Jin, Alan J. Tackett, Deyou Zheng, Gang Greg Wang

Neurology

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

Original language	English (US)
Article number	1045
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21357-3
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Li, J., Galbo, P. M., Gong, W., Storey, A. J., Tsai, Y. H., Yu, X., Ahn, J. H., Guo, Y., Mackintosh, S. G., Edmondson, R. D., Byrum, S. D., Farrar, J. E., He, S., Cai, L., Jin, J., Tackett, A. J., Zheng, D., & Wang, G. G. (2021). ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism. Nature communications, 12(1), Article 1045. https://doi.org/10.1038/s41467-021-21357-3

Li, J, Galbo, PM, Gong, W, Storey, AJ, Tsai, YH, Yu, X, Ahn, JH, Guo, Y, Mackintosh, SG, Edmondson, RD, Byrum, SD, Farrar, JE, He, S, Cai, L, Jin, J, Tackett, AJ, Zheng, D & Wang, GG 2021, 'ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism', Nature communications, vol. 12, no. 1, 1045. https://doi.org/10.1038/s41467-021-21357-3

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title = "ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism",

abstract = "Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-{\textquoteleft}reading{\textquoteright} bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.",

author = "Jie Li and Galbo, {Phillip M.} and Weida Gong and Storey, {Aaron J.} and Tsai, {Yi Hsuan} and Xufen Yu and Ahn, {Jeong Hyun} and Yiran Guo and Mackintosh, {Samuel G.} and Edmondson, {Ricky D.} and Byrum, {Stephanie D.} and Farrar, {Jason E.} and Shenghui He and Ling Cai and Jian Jin and Tackett, {Alan J.} and Deyou Zheng and Wang, {Gang Greg}",

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AU - Li, Jie

AU - Galbo, Phillip M.

AU - Gong, Weida

AU - Storey, Aaron J.

AU - Tsai, Yi Hsuan

AU - Yu, Xufen

AU - Ahn, Jeong Hyun

AU - Guo, Yiran

AU - Mackintosh, Samuel G.

AU - Edmondson, Ricky D.

AU - Byrum, Stephanie D.

AU - Farrar, Jason E.

AU - He, Shenghui

AU - Cai, Ling

AU - Jin, Jian

AU - Tackett, Alan J.

AU - Zheng, Deyou

AU - Wang, Gang Greg

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

AB - Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

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ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

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