@article{1cdc099355ce4a198b8416538e819feb,
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}",
note = "Funding Information: We graciously thank BD Strahl, R Rottapel, MP Kamps and Q Zhang for providing reagents used in the study and all members of the Wang Laboratory for helpful discussion and technical supports. We thank UNC core facilities, including High-throughput Sequencing Facility, Bioinformatics Core, Flow Cytometry Core, Animal Studies Core and Histology Research Core, for their professional support of this work. The cores affiliated to UNC Cancer Center are supported in part by the UNC Lineberger Comprehensive Cancer Center Core Support Grant P30-CA016086. This work utilized the AVANCE NEO 600 MHz NMR Spectrometer System that was upgraded with funding from a NIH SIG grant 1S10OD025132-01A1. We acknowledge proteomics support from the NIH IDeA National Resource for Quantitative Proteomics with funding through TL1TR003109, P20GM121293, R24GM137786, S10OD018445, and R01CA236209. This work was supported by NIH grants (R01-CA215284 and R01-CA211336 to G.G.W., R01GM122749 to J.J.), and grants of a Concern Foundation for Cancer Research grant (to G.G.W.), Gabrielle{\textquoteright}s Angel Foundation for Cancer Research (to G.G.W.), Gilead Sciences Research Scholars Program in hematology/ oncology (to G.G.W.) and When Everyone Survives (WES) Leukemia Research Foundation (to G.G.W.). G.G.W. is an American Cancer Society (ACS) Research Scholar, an American Society of Hematology (ASH) Scholar in basic science and a Leukemia and Lymphoma Society (LLS) Scholar. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1038/s41467-021-21357-3",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}