PRL-3, a Metastasis Associated Tyrosine Phosphatase, Is Involved in FLT3-ITD Signaling and Implicated in Anti-AML Therapy

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.

联合其他小分子药物是提升FLT3抑制剂（FLT3 inhibitor）临床治疗效果的颇具潜力的策略。本研究证实，将FLT3抑制剂ABT-869与HDAC抑制剂（HDAC inhibitor）SAHA联用，可协同杀伤携带FLT3突变的急性髓系白血病（Acute Myeloid Leukemia，AML）细胞，并抑制其集落形成。我们在两种不同的白血病细胞系中，鉴定出了仅由该联合治疗方案诱导的核心基因特征谱。其中，我们发现PTP4A3（PRL-3）的下调在该协同效应中发挥了关键作用。PRL-3位于FLT3信号通路的下游，异位表达PTP4A3可通过上调信号转导与转录激活因子（signal transducers and activators of transcription，STAT）通路活性以及抗凋亡蛋白Mcl-1的表达，引发治疗耐药。PRL-3可与HDAC4发生相互作用，而SAHA可通过蛋白酶体（proteasome）依赖途径下调PTP4A3的表达。此外，在47%的AML病例中可检测到PRL-3蛋白，但在正常骨髓的髓系细胞中未检测到该蛋白。本研究结果表明，此类联合疗法可显著提升FLT3抑制剂的临床治疗效果。PRL-3在AML中具有潜在的病理作用，有望成为AML的有效治疗靶点，值得开展临床研究。