PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-aml therapy

Jianbiao Zhou, Chonglei Bi, Wee Joo Chng, Lip Lee Cheong, Shaw Cheng Liu, Sylvia Mahara, Kian Ghee Tay, Qi Zeng, Jie Li, Ke Guo, Cheng Peow Bobby Tan, Hanry Yu, Daniel H. Albert, Chien Shing Chen

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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.

Original languageEnglish
Article numbere19798
JournalPLoS ONE
Volume6
Issue number5
DOIs
Publication statusPublished - 2011
Externally publishedYes

Cite this

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), [e19798]. https://doi.org/10.1371/journal.pone.0019798