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Since <jats:italic>NR4A1<\/jats:italic> abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of <jats:italic>NR4A3<\/jats:italic> may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and <jats:italic>NR4A3<\/jats:italic> expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on <jats:italic>NR4A3<\/jats:italic> expression and <jats:italic>NR4A3<\/jats:italic> knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of <jats:italic>NR4A3<\/jats:italic>, while <jats:italic>NR4A3<\/jats:italic> knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive <jats:italic>NR4A3<\/jats:italic> downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and <jats:italic>NR4A3<\/jats:italic> expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and <jats:italic>NR4A3<\/jats:italic> downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of <jats:italic>NR4A1<\/jats:italic> and <jats:italic>NR4A3.<\/jats:italic><\/jats:p>","DOI":"10.1007\/s00277-022-04961-1","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T12:02:51Z","timestamp":1661860971000},"page":"2209-2218","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis"],"prefix":"10.1007","volume":"101","author":[{"given":"Shih-Chiang","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Yuan","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-An","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Ting","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus J.","family":"Calkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Yeh","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jih-Luh","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwei-Fang","family":"Tien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0772-869X","authenticated-orcid":false,"given":"Shang-Ju","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,30]]},"reference":[{"key":"4961_CR1","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.2147\/CMAR.S242479","volume":"12","author":"F Pourrajab","year":"2020","unstructured":"Pourrajab F, Zare-Khormizi MR, Hashemi AS, Hekmatimoghaddam S (2020) Genetic characterization and risk stratification of acute myeloid leukemia. 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