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|Title:||PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-aml therapy||Authors:||Zhou, J.
|Issue Date:||2011||Citation:||Zhou, J., Bi, C., Chng, W.-J., Cheong, L.-L., Liu, S.-C., Mahara, S., Tay, K.-G., Zeng, Q., Li, J., Guo, K., Tan, C.P.B., Yu, H., Albert, D.H., Chen, C.-S. (2011). PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-aml therapy. PLoS ONE 6 (5) : -. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0019798||Abstract:||Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation. © 2011 Zhou et al.||Source Title:||PLoS ONE||URI:||http://scholarbank.nus.edu.sg/handle/10635/115242||ISSN:||19326203||DOI:||10.1371/journal.pone.0019798|
|Appears in Collections:||Staff Publications|
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