{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T10:04:07Z","timestamp":1771236247892,"version":"3.50.1"},"reference-count":68,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82070166"],"award-info":[{"award-number":["82070166"]}]},{"name":"National Natural Science Foundation of China","award":["BRA2019103"],"award-info":[{"award-number":["BRA2019103"]}]},{"name":"National Natural Science Foundation of China","award":["ZD2021003"],"award-info":[{"award-number":["ZD2021003"]}]},{"name":"Jiangsu Province \u201c333\u201d project","award":["82070166"],"award-info":[{"award-number":["82070166"]}]},{"name":"Jiangsu Province \u201c333\u201d project","award":["BRA2019103"],"award-info":[{"award-number":["BRA2019103"]}]},{"name":"Jiangsu Province \u201c333\u201d project","award":["ZD2021003"],"award-info":[{"award-number":["ZD2021003"]}]},{"name":"Medical research key projects\u2014Jiangsu Commission of Health","award":["82070166"],"award-info":[{"award-number":["82070166"]}]},{"name":"Medical research key projects\u2014Jiangsu Commission of Health","award":["BRA2019103"],"award-info":[{"award-number":["BRA2019103"]}]},{"name":"Medical research key projects\u2014Jiangsu Commission of Health","award":["ZD2021003"],"award-info":[{"award-number":["ZD2021003"]}]},{"name":"Milstein Medical Asian American Partnership (MMAAP) Foundation Research Project Award in Hematology (2017)","award":["82070166"],"award-info":[{"award-number":["82070166"]}]},{"name":"Milstein Medical Asian American Partnership (MMAAP) Foundation Research Project Award in Hematology (2017)","award":["BRA2019103"],"award-info":[{"award-number":["BRA2019103"]}]},{"name":"Milstein Medical Asian American Partnership (MMAAP) Foundation Research Project Award in Hematology (2017)","award":["ZD2021003"],"award-info":[{"award-number":["ZD2021003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is one of the most common hematological malignancies with high heterogeneity, characterized by a differentiating block at the early progenitor stage. The selective BCL-2 inhibitor, Venetoclax (Ven), has shown exciting clinical results in a certain group of AML patients. However, Ven alone is insufficient to reach an enduringly complete response, which leads to the concern of Ven resistance. Alternative combined therapies with Ven are demanded in AML. Here, we reported the synergistic effect and molecular mechanism of the enhancer of zeste homolog 2 (EZH2) inhibitor DZNeP with Ven in AML cells. Results showed that the combination of DZNeP with Ven significantly induces cell proliferation arrest compared to single-drug control in AML cells and primary samples, and CalcuSyn analysis showed their significant synergy. The combination also significantly promotes apoptosis and increases the expression of pro-apoptotic proteins. The whole transcriptome analysis showed that phosphoinositide-3-kinase-interacting protein1 (PIK3IP1), the PI3K\/AKT\/mTOR signaling suppressor, is upregulated upon DZNeP treatment. Moreover, EZH2 is upregulated but PIK3IP1 is downregulated in 88 newly diagnosed AML cohorts compared to 70 healthy controls, and a higher expression of EZH2 is associated with poor outcomes in AML patients. Particularly, the combination of DZNeP with Ven dramatically eliminated CD117 (c-KIT) (+) AML blasts, suggesting the effect of the combination on tumor stem cells. In summary, our data indicated that DZNeP increases the sensitivity of Ven in AML by affecting PI3K and c-KIT signaling in AML. Our results also suggested that the therapeutic targeting of both EZH2 and BCL-2 provides a novel potential combined strategy against AML.<\/jats:p>","DOI":"10.3390\/ijms231911393","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T23:12:12Z","timestamp":1664320332000},"page":"11393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Targeting EZH2 Promotes Chemosensitivity of BCL-2 Inhibitor through Suppressing PI3K and c-KIT Signaling in Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6727-8790","authenticated-orcid":false,"given":"Chan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8028-1612","authenticated-orcid":false,"given":"Zheng","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4081-2543","authenticated-orcid":false,"given":"Chunhua","family":"Song","sequence":"additional","affiliation":[{"name":"Hershey Medical Center, Pennsylvania State University Medical College, Hershey, PA 17033, USA"},{"name":"Division of Hematology, The Ohio State University Wexner Medical Center, The James Cancer Hospital, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1038\/bcj.2016.50","article-title":"Acute myeloid leukemia: A comprehensive review and 2016 update","volume":"6","author":"Kouchkovsky","year":"2016","journal-title":"Blood Cancer J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10552-007-9097-2","article-title":"Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997\u20132002","volume":"19","author":"Yamamoto","year":"2008","journal-title":"Cancer Causes Control"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/bjh.12425","article-title":"Survival and cure of acute myeloid leukemia in England, 1971\u20132006: A population-based study","volume":"162","author":"Shah","year":"2013","journal-title":"Br. 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