@article{3163328c22074435b5b09e84a92a3029,
title = "A PRC2-Kdm5b axis sustains tumorigenicity of acute myeloid leukemia",
abstract = "Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or mixed lineage leukemia (MLL) rearrangement (MLL-r) share transcriptomic profiles associated with stemness-related gene signatures and display poor prognosis. The molecular underpinnings of AML aggressiveness and stemness remain far from clear. Studies with EZH2 enzymatic inhibitors show that polycomb repressive complex 2 (PRC2) is crucial for tumorigenicity in NUP98-NSD1+ AML, whereas transcriptomic analysis reveal that Kdm5b, a lysine demethylase gene carrying “bivalent” chromatin domains, is directly repressed by PRC2. While ectopic expression of Kdm5b suppressed AML growth, its depletion not only promoted tumorigenicity but also attenuated anti-AML effects of PRC2 inhibitors, demonstrating a PRC2–jKdm5b axis for AML oncogenesis. Integrated RNA sequencing (RNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and Cleavage Under Targets & Release Using Nuclease (CUT&RUN) profiling also showed that Kdm5b directly binds and represses AML stemness genes. The anti-AML effect of Kdm5b relies on its chromatin association and/or scaffold functions rather than its demethylase activity. Collectively, this study describes a molecular axis that involves histone modifiers (PRC2–jKdm5b) for sustaining AML oncogenesis.",
keywords = "AML, Kdm5b, PRC2, Stemness, Tumorigenicity",
author = "Zhihong Ren and Arum Kim and Huang, {Yu Ting} and Pi, {Wen Chieh} and Weida Gong and Xufen Yu and Jun Qi and Jian Jin and Ling Cai and Roeder, {Robert G.} and Chen, {Wei Yi} and Wang, {Gang Greg}",
note = "Funding Information: We thank Drs. Qin Yan and David L. Bentley for providing reagents used in the study and all laboratory members for discussion and technical support. We sincerely thank UNC facilities, including the High-Throughput Sequencing Facility, Bioinformatics Core, Flow Cytometry Core, Tissue Culture Facility, and Animal Studies Core, for their professional assistance of this work. The cores affiliated with the UNC Cancer Center are supported in part by the UNC Lineberger Comprehensive Cancer Center Core Support Grant P30-CA016086. The publicly available The Cancer Genome Atlas (TCGA) dataset used here is in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This work was supported by NIH (CA178765, to R.G.R.), the Leukemia and Lymphoma Society Specialized Center of Research Grant (17403-19, to R.G.R.), the Gilead Sciences Research Scholars Program in hematology/oncology (to G.G.W.), When Everyone Survives Leukemia Research Foundation (to G.G.W.), the Ministry of Science and Technology in Taiwan (MOST 107-2320-B-010-024-MY3 and 110-2320-B-A49A-533-MY3, to W.-Y.C.), and the Cancer Progression Research Center, National Yang Ming Chiao Tung University, from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan (to W.-Y.C.). Funding Information: ACKNOWLEDGMENTS. We thank Drs. Qin Yan and David L. Bentley for providing reagents used in the study and all laboratory members for discussion and technical support. We sincerely thank UNC facilities, including the High-Throughput Sequencing Facility, Bioinformatics Core, Flow Cytometry Core, Tissue Culture Facility, and Animal Studies Core, for their professional assistance of this work. The cores affiliated with the UNC Cancer Center are supported in part by the UNC Lineberger Comprehensive Cancer Center Core Support Grant P30-CA016086. The publicly available The Cancer Genome Atlas (TCGA) dataset used here is in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This work was supported by NIH (CA178765, to R.G.R.), the Leukemia and Lymphoma Society Specialized Center of Research Grant (17403-19, to R.G.R.), the Gilead Sciences Research Scholars Program in hematology/oncology (to G.G.W.), When Everyone Survives Leukemia Research Foundation (to G.G.W.), the Ministry of Science and Technology in Taiwan (MOST 107-2320-B-010-024-MY3 and 110-2320-B-A49A-533-MY3, to W.-Y.C.), and the Cancer Progression Research Center, National Yang Ming Chiao Tung University, from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan (to W.-Y.C.). Publisher Copyright: {\textcopyright} 2022 National Academy of Sciences. All rights reserved.",
year = "2022",
month = mar,
day = "1",
doi = "10.1073/pnas.2122940119",
language = "English",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "9",
}