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Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proli...

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Autores principales: Lin, Shih-Chiang, Yao, Chi-Yuan, Hsu, Cheng-An, Lin, Chien-Ting, Calkins, Marcus J., Kuo, Yuan-Yeh, Tang, Jih-Luh, Tien, Hwei-Fang, Wu, Shang-Ju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463347/
https://www.ncbi.nlm.nih.gov/pubmed/36040481
http://dx.doi.org/10.1007/s00277-022-04961-1
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author Lin, Shih-Chiang
Yao, Chi-Yuan
Hsu, Cheng-An
Lin, Chien-Ting
Calkins, Marcus J.
Kuo, Yuan-Yeh
Tang, Jih-Luh
Tien, Hwei-Fang
Wu, Shang-Ju
author_facet Lin, Shih-Chiang
Yao, Chi-Yuan
Hsu, Cheng-An
Lin, Chien-Ting
Calkins, Marcus J.
Kuo, Yuan-Yeh
Tang, Jih-Luh
Tien, Hwei-Fang
Wu, Shang-Ju
author_sort Lin, Shih-Chiang
collection PubMed
description The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 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 NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 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 NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00277-022-04961-1.
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spelling pubmed-94633472022-09-11 Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis Lin, Shih-Chiang Yao, Chi-Yuan Hsu, Cheng-An Lin, Chien-Ting Calkins, Marcus J. Kuo, Yuan-Yeh Tang, Jih-Luh Tien, Hwei-Fang Wu, Shang-Ju Ann Hematol Original Article The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 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 NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 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 NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00277-022-04961-1. Springer Berlin Heidelberg 2022-08-30 2022 /pmc/articles/PMC9463347/ /pubmed/36040481 http://dx.doi.org/10.1007/s00277-022-04961-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Lin, Shih-Chiang
Yao, Chi-Yuan
Hsu, Cheng-An
Lin, Chien-Ting
Calkins, Marcus J.
Kuo, Yuan-Yeh
Tang, Jih-Luh
Tien, Hwei-Fang
Wu, Shang-Ju
Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis
title Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis
title_full Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis
title_fullStr Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis
title_full_unstemmed Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis
title_short Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis
title_sort functional association of nr4a3 downregulation with impaired differentiation in myeloid leukemogenesis
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463347/
https://www.ncbi.nlm.nih.gov/pubmed/36040481
http://dx.doi.org/10.1007/s00277-022-04961-1
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