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Phosphatase PRL2 promotes oncogenic NOTCH1-Induced T-cell leukemia

Leukemia volume 31, pages 751–754 (2017)Cite this article

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Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs.1 T-cell acute lymphoblastic leukemia (T-ALL) is characterized by outgrowth of immature T cells.1 Gain-of-function mutations in NOTCH1 are common in T-ALL,2 making this receptor a promising target for drugs such as γ-secretase inhibitors (GSIs), which can block a proteolytic cleavage required for NOTCH1 activation.3 However, the enthusiasm for these therapies has been tempered by tumor resistance and paucity of information on the oncogenic programs regulated by oncogenic NOTCH1.3, 4 Therefore, the purpose of this study was to identify oncogenic NOTCH1-mediated molecular and genetic changes that contribute to T-ALL for future targeted therapies in order to improve leukemia treatment.

The phosphatase of regenerating liver (PRL) family of phosphatases, consisting of PRL1, PRL2 and PRL3, represents an intriguing group of proteins that are currently being validated as potential biomarkers and therapeutic targets in human cancer, including breast cancer, ovarian cancer and lung cancer.5 Notably, recent findings indicate that PRLs have important roles in the pathogenesis of hematological malignancies.6 For instance, PRL3 is highly expressed in BCR-ABL-positive ALL, which may be responsible for the aggressive phenotype of the disease.7 PRL2 is located on human chromosome 1p35, a region often rearranged or amplified in malignant lymphoma and B-cell chronic lymphocytic leukemia (B-CLL).5 PRL2 mRNA is also highly expressed in primary human acute myeloid leukemia (AML) and T-ALL cells, suggesting that PRL2 may play an important role in the pathogenesis of T-ALL.8, 9 We recently generated Prl2-deficient mice and found that PRL2 is required for extra-embryonic development by negatively regulating PTEN, thereby activating the PI3K-Akt pathway.10 In a previous study, we observed that PRL2 enhances hematopoietic stem and progenitor cell (HSPC) proliferation through mediating SCF/KIT signaling.11 These findings suggest that PRLs may represent novel therapeutic targets for the treatment of hematological malignancies.6, 7, 8, 9, 10, 11

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Acknowledgements

This work was supported in part by National Institutes of Health Grant CA69202 (Z-YZ), Department of Defense Grant W81XWH-13-1-0187 (YL), a St Baldrick’s Foundation Scholar Award (YL), an Elsa Pardee Foundation New Investigator Award (YL), an Alex’s Lemonade Stand Foundation Grant (YL), a Children’s Leukemia Research Association Grant (YL), a Leukemia Research Foundation grant (YL), and American Cancer Society Institutional Research Grants (YL and MK). This work was supported in part by a Project Development Team within the ICTSI NIH/NCRR Grant Number UL1TR001108.

Author contributions

MK, YB, Z-YZ and YL designed the research. MK, YB, SC, RG, CY and WC performed the research. MK and YL analyzed the data and performed the statistical analysis. AAC and JC provided reagents to the study. MK and YL wrote the manuscript. All authors read, comment on and approved the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    M Kobayashi, R Gao, W Cai, A A Cardoso, J Croop & Y Liu

  2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    Y Bai, S Chen, Z-Y Zhang & Y Liu

  3. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA

    Y Bai & Z-Y Zhang

  4. Department of Rheumatology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    C Yao

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  1. M Kobayashi
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Corresponding authors

Correspondence to Z-Y Zhang or Y Liu.

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Kobayashi, M., Bai, Y., Chen, S. et al. Phosphatase PRL2 promotes oncogenic NOTCH1-Induced T-cell leukemia. Leukemia 31, 751–754 (2017). https://doi.org/10.1038/leu.2016.340

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