Yamatani, KotokoAi, TomohikoSaito, KaoriSuzuki, KoyaHori, AtsushiKinjo, SonokoIkeo, KazuhoRuvolo, VivianZhang, WeiguoMak, Po YeeKaczkowski, BogumilHarada, HironoriKatayama, KazuhiroSugimoto, YoshikazuMyslinski, JeredHato, TakashiMiida, TakashiKonopleva, MarinaHayashizaki, YoshihideCarter, Bing Z.Tabe, YokoAndreeff, Michael2023-05-152023-05-152022Yamatani K, Ai T, Saito K, et al. Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML. Transl Oncol. 2022;18:101354. doi:10.1016/j.tranon.2022.101354https://hdl.handle.net/1805/32951Tyrosine 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalVenetoclaxAcute myeloid leukemiaTyrosine kinase inhibitorsCap analysis gene expressionArticle