TY - JOUR
T1 - Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells
AU - Morita, Ken
AU - Noura, Mina
AU - Tokushige, Chieko
AU - Maeda, Shintaro
AU - Kiyose, Hiroki
AU - Kashiwazaki, Gengo
AU - Taniguchi, Junichi
AU - Bando, Toshikazu
AU - Yoshida, Kenichi
AU - Ozaki, Toshifumi
AU - Matsuo, Hidemasa
AU - Ogawa, Seishi
AU - Liu, Pu Paul
AU - Nakahata, Tatsutoshi
AU - Sugiyama, Hiroshi
AU - Adachi, Souichi
AU - Kamikubo, Yasuhiko
N1 - Funding Information:
This work was supported by Grant-in-Aid for Scientific Research (KAKENHI), We thank Dr. H. Miyoshi (RIKEN, BRC) for kindly providing lentivirus vectors encoding CSII-EF-MCS-IRES2-Venus, CSII-EF-MCS-IRES2-hKO1 and CSIV-TRE-Ubc-KT.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-017-16799-z
DO - 10.1038/s41598-017-16799-z
M3 - Article
C2 - 29192243
AN - SCOPUS:85036662473
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 16604
ER -