Browsing by Author "Andreeff, Michael"

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    Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML
    (Elsevier, 2022) 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; Medicine, School of Medicine
    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.
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    The organic arsenic derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells
    (International Institute of Anticancer Research, 2012-07) Cheng, Xiaodong; Quintas-Cardama, Alfonso; Golemovic, Mirna; Zingaro, Ralph; Gao, Ming-Zhang; Freireich, Emil J.; Andreeff, Michael; Kantarjian, Hagop M.; Verstovsek, Srdan; Department of Radiology and Imaging Sciences, IU School of Medicine
    Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML.