@article{bb47e32ded2d4ba2ac69a791d841a75e,
title = "Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML",
abstract = "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.",
keywords = "AML, BCL2A1, CAGE, FLT3, Venetoclax",
author = "Kotoko Yamatani and Tomohiko Ai and Kaori Saito and Koya Suzuki and Atsushi Hori and Sonoko Kinjo and Kazuho Ikeo and Vivian Ruvolo and Weiguo Zhang and Mak, {Po Yee} and Bogumil Kaczkowski and Hironori Harada and Kazuhiro Katayama and Yoshikazu Sugimoto and Jered Myslinski and Takashi Hato and Takashi Miida and Marina Konopleva and Yoshihide Hayashizaki and Carter, {Bing Z.} and Yoko Tabe and Michael Andreeff",
note = "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: {\textcopyright} 2022",
year = "2022",
month = apr,
doi = "10.1016/j.tranon.2022.101354",
language = "English (US)",
volume = "18",
journal = "Translational Oncology",
issn = "1944-7124",
publisher = "Neoplasia Press",
}