RRC ID 50018
Author Morita K, Noura M, Tokushige C, Maeda S, Kiyose H, Kashiwazaki G, Taniguchi J, Bando T, Yoshida K, Ozaki T, Matsuo H, Ogawa S, Liu PP, Nakahata T, Sugiyama H, Adachi S, Kamikubo Y.
Title Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells.
Journal Sci Rep
Abstract Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-β (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.
Volume 7(1)
Pages 16604
Published 2017-11-30
DOI 10.1038/s41598-017-16799-z
PII 10.1038/s41598-017-16799-z
PMID 29192243
PMC PMC5709397
MeSH Antineoplastic Agents / pharmacology Cell Line, Tumor Core Binding Factor Alpha 2 Subunit / genetics Core Binding Factor Alpha 2 Subunit / metabolism* Core Binding Factor beta Subunit / genetics Core Binding Factor beta Subunit / metabolism* Drug Resistance, Neoplasm / genetics Gene Expression Regulation, Leukemic Humans Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / metabolism* Models, Biological RNA, Small Interfering / genetics Signal Transduction* Transcription, Genetic Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism*
IF 4.011
Times Cited 6
DNA material pENTR4-H1tetOx1 (RDB07916) CS-RfA-ETBsd (RDB07917) CS-RfA-ETV (RDB08020) CS-RfA-ETR (RDB08362) CSII-EF-MCS-IRES2-Venus (RDB04384) CSII-EF-MCS-IRES2-hKO1 (RDB07915).