Page 105 - 2019_08-Haematologica-web

Acute Myeloid Leukemia
RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4- mediated transactivation of P57
Shuang Liu,1* Yanyan Xing,1* Wenting Lu,1 Shouyun Li,1 Zheng Tian,1 Haiyan Xing,1 Kejing Tang,1 Yingxi Xu,1 Qing Rao,1 Min Wang1
and Jianxiang Wang1,2
1State Key Laboratory of Experimental Hematology and 2National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P.R. China
ABSTRACT
RUNX1 is a key transcription factor in hematopoiesis and its disrup- tion 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 tar- gets, 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 strate- gies for RUNX1-altered leukemia. In this study, we identified and con- firmed 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 leuke- mogenic RUNX1-ETO fusion protein had little effect on this transactiva- tion. KLF4 was also identified as a novel binding partner of RUNX1. RUNX1 interacted with KLF4 through Runt domain and further co-activat- ed 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 prolif- eration 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.
Introduction
RUNX1, also known as AML1 and CBFα, is a critical transcription factor in hematopoiesis, which regulates various kinds of hematopoiesis-related genes, including cytokines, cytokine receptors, microRNA and other transcription factors.1 It is very versatile and also interacts with a number of other hematopoietic regula- tors, such as CBFβ, PU.1, GATA1, PAX5, and ETS1.2-6 These interaction partners provide RUNX1 with the potential to target genes primarily regulated by other transcription factors, and vice versa. RUNX1 is frequently involved in gene muta- tions and chromosomal translocations in leukemias, which indicates that the altered function of RUNX1 is closely related with leukemogenesis. Among them, t(8;21)(q22;q22) is one of the most common chromosomal translocations in acute myeloid leukemia (AML), which results in RUNX1-ETO fusion protein. RUNX1- ETO fuses the N-terminus of RUNX1 including only runt domain (RHD) in-frame with the almost entire ETO protein. This leukemogenic fusion protein competes with wild-type RUNX1 in binding to its target genes and recruits a transcriptional co-repressor complex NCoR/SMRT/HDAC to further repress transcription of RUNX1 target genes.7-9 The dominant negative repressive effects of RUNX1-ETO on RUNX1 is considered to be the major pathogenic mechanism of t(8;21) AML, which causes blockage of normal hematopoietic differentiation and accumulation of immature myelocytes.10
Ferrata Storti Foundation
Haematologica 2019 Volume 104(8):1597-1607
*These authors contributed equally to this work.
Correspondence:
JIANXIANG WANG
wangjx@ihcams.ac.cn
MIN WANG
wangjxm@ihcams.ac.cn
Received: March 5, 2018. Accepted: February 20, 2019. Pre-published: February 21, 2019.
doi:10.3324/haematol.2018.192773
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/8/1597
©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 inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(8)
1597
ARTICLE