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

Abstract

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.

• Authors: Shuang Liu, Yanyan Xing, Wenting Lu, Shouyun Li, Zheng Tian, Haiyan Xing, Kejing Tang, Yingxi Xu, Qing Rao, Min Wang, Jianxiang Wang
• Journal: Haematologica (Haematologica) Vol. 104 Issue 8 Pg. 1597-1607 (08 2019) ISSN: 1592-8721 [Electronic] Italy
• PMID: 30792202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2019 Ferrata Storti Foundation.

Chemical References

• CDKN1C protein, human
• Core Binding Factor Alpha 2 Subunit
• Cyclin-Dependent Kinase Inhibitor p57
• KLF4 protein, human
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Oncogene Proteins, Fusion
• RNA, Long Noncoding
• RUNX1 protein, human
• RUNX1-IT1 long non-coding RNA, human

Topics

• Apoptosis (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Chromosomes, Human, Pair 21
• Chromosomes, Human, Pair 8
• Core Binding Factor Alpha 2 Subunit (metabolism)
• Cyclin-Dependent Kinase Inhibitor p57 (metabolism)
• Gene Expression Regulation, Leukemic
• Humans
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Leukemia, Myeloid, Acute (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics)
• Protein Binding
• Protein Interaction Domains and Motifs
• RNA, Long Noncoding
• Transcriptional Activation
• Translocation, Genetic