Please use this identifier to cite or link to this item: https://doi.org/10.1038/sj.leu.2404960
Title: Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway
Authors: Zhou, J. 
Pan, M.
Xie, Z. 
Loh, S.-L.
Bi, C.
Tai, Y.-C.
Lilly, M.
Lim, Y.-P. 
Han, J.-H.
Glaser, K.B.
Albert, D.H.
Davidsen, S.K.
Chen, C.-S.
Issue Date: Jan-2008
Citation: Zhou, J., Pan, M., Xie, Z., Loh, S.-L., Bi, C., Tai, Y.-C., Lilly, M., Lim, Y.-P., Han, J.-H., Glaser, K.B., Albert, D.H., Davidsen, S.K., Chen, C.-S. (2008-01). Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway. Leukemia 22 (1) : 138-146. ScholarBank@NUS Repository. https://doi.org/10.1038/sj.leu.2404960
Abstract: Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor play an important role in the pathogenesis of acute myeloid leukemia (AML) and represent an attractive therapeutic target. ABT-869 has demonstrated potent effects in AML cells with FLT3-ITDs. Here, we provide further evidence that ABT-869 treatment significantly downregulates cyclins D and E but increases the expression of p21 and p27. ABT-869 induces apoptosis through downregulation of Bcl-xL and upregulation of BAK, BID and BAD. We also evaluate the combinations of ABT-869 and chemotherapy. ABT-869 demonstrates significant sequence-dependent synergism with cytarabine and doxorubicin in cell lines and primary leukemia samples. The optimal combination was validated in MV4-11 xenografts. Low-density array analysis revealed the synergistic interaction involved in downregulation of cell cycle and mitogen-activated protein kinase pathway genes. CCND1 and c-Mos were the most significantly inhibited targets on both transcriptional and translational levels. Treatment with short hairpin RNAs targeting either CCND1 or c-Mos further sensitized MV4-11 cells to ABT-869. These findings suggest that specific pathway genes were further targeted by adding chemotherapy and support the rationale of combination therapy. Thus, a clinical trial using sequence-dependent combination therapy with ABT-869 in AML is warranted.
Source Title: Leukemia
URI: http://scholarbank.nus.edu.sg/handle/10635/108562
ISSN: 08876924
DOI: 10.1038/sj.leu.2404960
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