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

• Published in: Translational oncology Vol. 18; p. 101354
• Main Authors: Yamatani, Kotoko, Ai, Tomohiko, Saito, Kaori, Suzuki, Koya, Hori, Atsushi, Kinjo, Sonoko, Ikeo, Kazuho, Ruvolo, Vivian, Zhang, Weiguo, Mak, Po Yee, Kaczkowski, Bogumil, Harada, Hironori, Katayama, Kazuhiro, Sugimoto, Yoshikazu, Myslinski, Jered, Hato, Takashi, Miida, Takashi, Konopleva, Marina, Hayashizaki, Yoshihide, Carter, Bing Z., Tabe, Yoko, Andreeff, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2022; Neoplasia Press; Elsevier
• Subjects: AML; BCL2A1; CAGE; FLT3; Original Research; Venetoclax; AML; CAGE; BCL2A1; FLT3; Venetoclax
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2022.101354

•BCL2A1 is upregulated and exerts a pro-survival function in FLT3-ITD/D835 AML cells.•Upregulation of BCL2A1 attenuates sensitivity to quizartinib in FLT3-ITD/D835 cells.•Gilteritinib decreases BCL2A1 through inactivation of STAT5 in FLT3-ITD/D835 cells.•Gilteritinib/Venetoclax has a synergistic anti-tumor activity in FLT3-ITD/D835 cells. 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.