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Cho, Byung-Sik; Zeng, Zhihong; Mu, Hong; Wang, Zhiqiang; Konoplev, Sergej; McQueen, Teresa; Protopopova, Marina; Cortes, Jorge; Marszalek, Joseph R.; Peng, Sheng-Bin; Ma, Wencai; Davis, R. Eric; Thornton, Donald E.; Andreeff, Michael; Konopleva, Marina
Blood, 07/2015, Letnik: 126, Številka: 2Journal Article
Targeting the stromal cell–derived factor 1α (SDF-1α)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell–derived factor 1 (SDF-1)α–induced chemotaxis and prosurvival signals of AML cells at nanomolar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1α/CXCR4 signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and β-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1α/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications. •In vitro, SDF-1α/CXCR4 inhibition by LY2510924 is potent and prolonged and inhibits proliferation and stromal chemoprotection of AML cells.•In vivo, LY2510924 mobilizes AML cells, has striking antileukemia effects as monotherapy, and strongly synergizes with chemotherapy.
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in: SICRIS
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