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RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57

RUNX1 is a key transcription factor in hematopoiesis and its disruption is one of the most common aberrations in acute myeloid leukemia. RUNX1 alterations affect its DNA binding capacity and transcriptional activities, leading to the deregulation of transcriptional targets, and abnormal proliferatio...

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Autores principales: Liu, Shuang, Xing, Yanyan, Lu, Wenting, Li, Shouyun, Tian, Zheng, Xing, Haiyan, Tang, Kejing, Xu, Yingxi, Rao, Qing, Wang, Min, Wang, Jianxiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669147/
https://www.ncbi.nlm.nih.gov/pubmed/30792202
http://dx.doi.org/10.3324/haematol.2018.192773
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author Liu, Shuang
Xing, Yanyan
Lu, Wenting
Li, Shouyun
Tian, Zheng
Xing, Haiyan
Tang, Kejing
Xu, Yingxi
Rao, Qing
Wang, Min
Wang, Jianxiang
author_facet Liu, Shuang
Xing, Yanyan
Lu, Wenting
Li, Shouyun
Tian, Zheng
Xing, Haiyan
Tang, Kejing
Xu, Yingxi
Rao, Qing
Wang, Min
Wang, Jianxiang
author_sort Liu, Shuang
collection PubMed
description RUNX1 is a key transcription factor in hematopoiesis and its disruption is one of the most common aberrations in acute myeloid leukemia. RUNX1 alterations affect its DNA binding capacity and transcriptional activities, leading to the deregulation of transcriptional targets, and abnormal proliferation and differentiation of myeloid cells. Identification of RUNX1 target genes and clarification of their biological functions are of great importance in the search for new therapeutic strategies for RUNX1-altered leukemia. In this study, we identified and confirmed that KLF4, a known tumor suppressor gene, as a direct target of RUNX1, was down-regulated in RUNX1-ETO leukemia. RUNX1 bound to KLF4 promoter in chromatin to activate its transcription, while the leukemogenic RUNX1-ETO fusion protein had little effect on this transactivation. KLF4 was also identified as a novel binding partner of RUNX1. RUNX1 interacted with KLF4 through Runt domain and further co-activated its target genes. However, RUNX1-ETO competed with RUNX1 to bind KLF4 through Runt and ETO domains, and abrogated transcription of KLF4. Finally, overexpression experiments indicated that RUNX1 inhibited proliferation and induced apoptosis of t(8;21) leukemia cells via KLF4-mediated upregulation of P57. These data suggest KLF4 dysregulation mediated by RUNX1-ETO enhances proliferation and retards apoptosis, and provides a potential target for therapy of t(8;21) acute myeloid leukemia.
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spelling pubmed-66691472019-08-22 RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57 Liu, Shuang Xing, Yanyan Lu, Wenting Li, Shouyun Tian, Zheng Xing, Haiyan Tang, Kejing Xu, Yingxi Rao, Qing Wang, Min Wang, Jianxiang Haematologica Article RUNX1 is a key transcription factor in hematopoiesis and its disruption is one of the most common aberrations in acute myeloid leukemia. RUNX1 alterations affect its DNA binding capacity and transcriptional activities, leading to the deregulation of transcriptional targets, and abnormal proliferation and differentiation of myeloid cells. Identification of RUNX1 target genes and clarification of their biological functions are of great importance in the search for new therapeutic strategies for RUNX1-altered leukemia. In this study, we identified and confirmed that KLF4, a known tumor suppressor gene, as a direct target of RUNX1, was down-regulated in RUNX1-ETO leukemia. RUNX1 bound to KLF4 promoter in chromatin to activate its transcription, while the leukemogenic RUNX1-ETO fusion protein had little effect on this transactivation. KLF4 was also identified as a novel binding partner of RUNX1. RUNX1 interacted with KLF4 through Runt domain and further co-activated its target genes. However, RUNX1-ETO competed with RUNX1 to bind KLF4 through Runt and ETO domains, and abrogated transcription of KLF4. Finally, overexpression experiments indicated that RUNX1 inhibited proliferation and induced apoptosis of t(8;21) leukemia cells via KLF4-mediated upregulation of P57. These data suggest KLF4 dysregulation mediated by RUNX1-ETO enhances proliferation and retards apoptosis, and provides a potential target for therapy of t(8;21) acute myeloid leukemia. Ferrata Storti Foundation 2019-08 /pmc/articles/PMC6669147/ /pubmed/30792202 http://dx.doi.org/10.3324/haematol.2018.192773 Text en Copyright© 2019 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Article
Liu, Shuang
Xing, Yanyan
Lu, Wenting
Li, Shouyun
Tian, Zheng
Xing, Haiyan
Tang, Kejing
Xu, Yingxi
Rao, Qing
Wang, Min
Wang, Jianxiang
RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57
title RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57
title_full RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57
title_fullStr RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57
title_full_unstemmed RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57
title_short RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57
title_sort runx1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via klf4-mediated transactivation of p57
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669147/
https://www.ncbi.nlm.nih.gov/pubmed/30792202
http://dx.doi.org/10.3324/haematol.2018.192773
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