NOVEL ROLE OF PRL-3 PHOSPHATASE IN HEMATOLOGICAL MALIGNANCIES

Abstract

Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in newly diagnosed multiple myeloma (MM) patients. However, the regulation and oncogenic activities of PRL-3 in MM warrants further investigation. Here, we report that IL-6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and re-phosphorylates STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity and tumorigenesis, and detailed mechanistic studies revealed a “de-activation” of effector proteins such as Akt, Erk1/2, Src, STAT1 and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-myc and mcl-1, and anti-apoptotic genes bcl-2 and bcl-xl. We also demonstrated a role of PRL-3 in the acquired resistance of myeloma cells towards bortezomib, which can be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression is positively correlated in five independent cohorts, and STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PTP4A3 is a biomarker to identify high-risk MM patients that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (PI and IMiD). Conclusively, our results supported a feedforward mechanism between STAT3 and PRL-3 that prolongs pro-survival signaling in MM, and proposed the targeting of PRL-3 as a validated therapeutic opportunity in MM.