TY - JOUR
T1 - Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML
AU - Yamatani, Kotoko
AU - Ai, Tomohiko
AU - Saito, Kaori
AU - Suzuki, Koya
AU - Hori, Atsushi
AU - Kinjo, Sonoko
AU - Ikeo, Kazuho
AU - Ruvolo, Vivian
AU - Zhang, Weiguo
AU - Mak, Po Yee
AU - Kaczkowski, Bogumil
AU - Harada, Hironori
AU - Katayama, Kazuhiro
AU - Sugimoto, Yoshikazu
AU - Myslinski, Jered
AU - Hato, Takashi
AU - Miida, Takashi
AU - Konopleva, Marina
AU - Hayashizaki, Yoshihide
AU - Carter, Bing Z.
AU - Tabe, Yoko
AU - Andreeff, Michael
N1 - Funding Information:
The authors wish to thank the Laboratory of Molecular and Biochemical Research and Research Support Center at Juntendo University Graduate School of Medicine for technical assistance. We are also grateful to Dr. Toshiaki Takano and Dr. Hidetaka Eguchi from Intractable Disease Research Center at Juntendo University Graduate School of Medicine for technical assistance. The authors would also like to thank Dr. Numsen Hail for assistance in editing the manuscript, Dr. Kaoru Mogushi, Dr. Masaki Hosoya, and Dr. Shigeo Yamaguchi for useful discussions.
Funding Information:
This work was supported in part by Grants-in Aid for Scientific Research (18J22436 to KY, 18K07424 to YT), International Joint Research Programs (19KK0221 to YT) from Japan Society for the Promotion of Science. This research was also partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (B Platform for Drug Discovery, Informatics, and Structural Life Science), and the Japan Agency for Medical Research and Development (AMED). Additional support was provided by the MD Anderson MDS/AML moonshot program, the CPRIT MIRA grant and funds from the Endowed Haas Chair in Genetics (all to MA).
Publisher Copyright:
© 2022
PY - 2022/4
Y1 - 2022/4
N2 - Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed that the gene expression of BCL2A1 transcription start sites was increased in primary AML cells bearing FLT3-ITD/D835 compared to FLT3-ITD. Overexpression of BCL2A1 attenuated the sensitivity to quizartinib, a type II TKI, and venetoclax, a selective BCL2 inhibitor, in AML cell lines. However, a type I TKI, gilteritinib, inhibited the expression of BCL2A1 through inactivation of STAT5 and alleviated TKI resistance of FLT3-ITD/D835. The combination of gilteritinib and venetoclax showed synergistic effects in the FLT3-ITD/D835 positive AML cells. The promoter region of BCL2A1 contains a BRD4 binding site. Thus, the blockade of BRD4 with a BET inhibitor (CPI-0610) downregulated BCL2A1 in FLT3-mutated AML cells and extended profound suppression of FLT3-ITD/D835 mutant cells. Therefore, we propose that BCL2A1 has the potential to be a novel therapeutic target in treating FLT3-ITD/D835 mutated AML.
AB - Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed that the gene expression of BCL2A1 transcription start sites was increased in primary AML cells bearing FLT3-ITD/D835 compared to FLT3-ITD. Overexpression of BCL2A1 attenuated the sensitivity to quizartinib, a type II TKI, and venetoclax, a selective BCL2 inhibitor, in AML cell lines. However, a type I TKI, gilteritinib, inhibited the expression of BCL2A1 through inactivation of STAT5 and alleviated TKI resistance of FLT3-ITD/D835. The combination of gilteritinib and venetoclax showed synergistic effects in the FLT3-ITD/D835 positive AML cells. The promoter region of BCL2A1 contains a BRD4 binding site. Thus, the blockade of BRD4 with a BET inhibitor (CPI-0610) downregulated BCL2A1 in FLT3-mutated AML cells and extended profound suppression of FLT3-ITD/D835 mutant cells. Therefore, we propose that BCL2A1 has the potential to be a novel therapeutic target in treating FLT3-ITD/D835 mutated AML.
KW - AML
KW - BCL2A1
KW - CAGE
KW - FLT3
KW - Venetoclax
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UR - http://www.scopus.com/inward/citedby.url?scp=85123751882&partnerID=8YFLogxK
U2 - 10.1016/j.tranon.2022.101354
DO - 10.1016/j.tranon.2022.101354
M3 - Article
AN - SCOPUS:85123751882
SN - 1936-5233
VL - 18
JO - Translational Oncology
JF - Translational Oncology
M1 - 101354
ER -
