title: PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-AML therapy.
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.
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Jianbiao
authors: J
authors: Zhou
authors: Chonglei
authors: C
authors: Bi
authors: Wee-Joo
authors: WJ
authors: Chng
authors: Lip-Lee
authors: LL
authors: Cheong
authors: Shaw-Cheng
authors: SC
authors: Liu
authors: Sylvia
authors: S
authors: Mahara
authors: Kian-Ghee
authors: KG
authors: Tay
authors: Qi
authors: Q
authors: Zeng
authors: Jie
authors: J
authors: Li
authors: Ke
authors: K
authors: Guo
authors: Cheng Peow Bobby
authors: CP
authors: Tan
authors: Hanry
authors: H
authors: Yu
authors: Daniel H
authors: DH
authors: Albert
authors: Chien-Shing
authors: CS
authors: Chen
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