Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia

Aberrant activation of Wnt/beta-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to beta-catenin, promoting the nuclear accumulation of beta-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards beta-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to beta-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant beta-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients who are likely to benefit from treatment with beta-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or beta-catenin hyperactivation.