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LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML. (Mol Cancer Res, Dec 2016)

Zhou J1, Chan ZL2, Bi C2, Lu X2, Chong PS2, Chooi JY2, Cheong LL2, Liu SC2, Ching YQ2, Zhou Y2, Osato M2, Tan TZ2, Ng CH3, Ng SB4, Zeng Q5, Chng WJ6.

1 Medicine, Yong Loo Lin School of Medicine, National University of Singapore.
2 Cancer Science Institute of Singapore, National University of Singapore.
3 Hematology-Oncology, National University Cancer Institute, NUHS.
4 Pathology, National University Hospital.
5 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research).
6 Hematology-Oncology, National University Cancer Institute, NUHS

PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo. Furthermore, PRL-3 phosphatase-activity dependently upregulates LIN28B, a stem cell reprogramming factor, which, in turn, represses the let-7 microRNA family, inducing a stem cell-like transcriptional program. Notably, elevated levels of LIN28B protein independently associates with worse survival in AML patients. Thus, these results establish a novel signaling axis involving PRL-3/LIN28B/let-7, which confers stem-cell like properties to leukemia cells that is important for leukemogenesis.

IMPLICATIONS: The current study offers a rationale for targeting PRL-3 as a therapeutic approach for a subset of AML with poor prognosis.

PMID: 28011885