Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML

Kotoko Yamatani; Tomohiko Ai; Kaori Saito; Koya Suzuki; Atsushi Hori; Sonoko Kinjo; Kazuho Ikeo; Vivian Ruvolo; Weiguo Zhang; Po Yee Mak; Bogumil Kaczkowski; Hironori Harada; Kazuhiro Katayama; Yoshikazu Sugimoto; Jered Myslinski; Takashi Hato; Takashi Miida; Marina Konopleva; Yoshihide Hayashizaki; Bing Z Carter; Yoko Tabe; Michael Andreeff

doi:10.1016/j.tranon.2022.101354

Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML

Transl Oncol. 2022 Apr:18:101354. doi: 10.1016/j.tranon.2022.101354. Epub 2022 Feb 1.

Authors

Kotoko Yamatani¹, Tomohiko Ai¹, Kaori Saito¹, Koya Suzuki¹, Atsushi Hori², Sonoko Kinjo³, Kazuho Ikeo³, Vivian Ruvolo⁴, Weiguo Zhang⁴, Po Yee Mak⁴, Bogumil Kaczkowski⁵, Hironori Harada⁶, Kazuhiro Katayama⁷, Yoshikazu Sugimoto⁸, Jered Myslinski⁹, Takashi Hato⁹, Takashi Miida¹, Marina Konopleva¹⁰, Yoshihide Hayashizaki¹¹, Bing Z Carter⁴, Yoko Tabe¹², Michael Andreeff¹³

Affiliations

¹ Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
² Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
³ Center for Information Biology, National Institute of Genetics, Shizuoka, Japan.
⁴ Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77030, United States.
⁵ Preventive Medicine and Diagnosis Innovation Program, RIKEN Center for Life Science Technologies, Kanagawa, Japan.
⁶ Department of Hematology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁷ Laboratory of Molecular Targeted Therapeutics, School of Pharmacy, Nihon University, Chiba, Japan.
⁸ Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
⁹ Department of Medicine, Indiana University School of Medicine, Marion, IN, United States.
¹⁰ Department of Leukemia, Section of Leukemia Biology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
¹¹ Kabushiki Kaisya Dnaform, Yokohama, Japan.
¹² Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77030, United States; Department of Next Generation Hematology Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address: tabe@juntendo.ac.jp.
¹³ Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77030, United States. Electronic address: mandreef@mdanderson.org.

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.