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BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia.

ABSTRACT: Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.

SUBMITTER: Li Y

PROVIDER: S-EPMC5053622 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia.

Li Yulin Y Deutzmann Anja A Choi Peter S PS Fan Alice C AC Felsher Dean W DW

Oncotarget 20160501 19

Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of mi ...[more]

PMID: 27095570

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Project description:Acute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature B or T lymphocytes. Extensive studies have suggested an involvement of angiogenesis signaling in ALL progression and resistance to treatment. Thus, targeting angiogenesis with anti-angiogenic drugs may be a promising approach for ALL treatment. In this study, we investigated the effectiveness of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 in ALL cells.ALL cell lines were treated with different concentration of Apatinib and then CCK8 assay, flow cytometry were used to determine the IC50 value and cell apoptosis, respectively. The effect of Apatinib against primary ALL cells from 11 adult patients and normal counterparts were also analyzed by apoptosis with flow cytometry. Next, we used western bolting and mass cytometry (CyTOF) assay to explore the underlying mechanism of the cytotoxicity of Apatinib. Finally, the anti-leukemia activity was further evaluated in an in vivo xenograft model of ALL.Our results showed that Apatinib significantly inhibited cell growth and promoted apoptosis in both B and T lineage ALL cell lines in a dose- and time-dependent manner. The IC50 values of Apatinib against Nalm6, Reh, Jurkat and Molt4 for 48 h were 55.76 ± 13.19, 51.53 ± 10.74, 32.43 ± 5.58, 39.91 ± 9.88 ?mol/L, and for 72 h were 30.34 ± 2.65, 31.96 ± 3.92, 17.62 ± 5.90, and 17.65 ± 2.17 ?mol/L respectively. Similarly, Apatinib shows cytotoxic activity against primary adult ALL cells while sparing their normal counterparts in vitro. Moreover, Apatinib suppressed ALL growth and progression in an in vivo xenograft model. Mechanistically, Apatinib-induced cytotoxicity was closely associated with inhibition of VEGFR2 and its downstream signaling cascades, including the PI3 K, MAPK and STAT3 pathways.Our study indicates that Apatinib exerts its anti-leukemia effect by inducing apoptosis through suppressing the VEGFR2 signaling pathway, supporting a potential role for Apatinib in the treatment of ALL.

Dataset Information

BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia.

Publications

BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia.

Similar Datasets

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