Translational Oncology (Apr 2022)
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
Affiliations
- Kotoko Yamatani
- Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Tomohiko Ai
- Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Kaori Saito
- Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Koya Suzuki
- Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Atsushi Hori
- 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
- Sonoko Kinjo
- Center for Information Biology, National Institute of Genetics, Shizuoka, Japan
- Kazuho Ikeo
- Center for Information Biology, National Institute of Genetics, Shizuoka, Japan
- Vivian Ruvolo
- 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
- Weiguo Zhang
- 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
- Po Yee Mak
- 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
- Bogumil Kaczkowski
- Preventive Medicine and Diagnosis Innovation Program, RIKEN Center for Life Science Technologies, Kanagawa, Japan
- Hironori Harada
- Department of Hematology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Kazuhiro Katayama
- Laboratory of Molecular Targeted Therapeutics, School of Pharmacy, Nihon University, Chiba, Japan
- Yoshikazu Sugimoto
- Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan
- Jered Myslinski
- Department of Medicine, Indiana University School of Medicine, Marion, IN, United States
- Takashi Hato
- Department of Medicine, Indiana University School of Medicine, Marion, IN, United States
- Takashi Miida
- Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Marina Konopleva
- Department of Leukemia, Section of Leukemia Biology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Yoshihide Hayashizaki
- Kabushiki Kaisya Dnaform, Yokohama, Japan
- Bing Z. Carter
- 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
- Yoko Tabe
- 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; Corresponding authors at: 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.
- Michael Andreeff
- 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; Corresponding authors at: 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.
- Journal volume & issue
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Vol. 18
p. 101354
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.
