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Chronic Lymphocytic Leukemia

PTPROt-mediated regulation of p53/Foxm1 suppresses leukemic phenotype in a CLL mouse model

Leukemia volume 29, pages 1350–1359 (2015)Cite this article

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Abstract

The gene encoding PTPROt (truncated isoform of protein tyrosine phosphatase receptor-type O) is methylated and suppressed in chronic lymphocytc leukemia (CLL). PTPROt exhibits in vitro tumor-suppressor characteristics through the regulation of B-cell receptor (BCR) signaling. Here we generated transgenic (Tg) mice with B-cell-specific expression of PTPROt. Although lymphocyte development is normal in these mice, crossing them with TCL1 Tg mouse model of CLL results in a survival advantage compared with the TCL1 Tg mice. Gene expression profiling of splenic B-lymphocytes before detectable signs of CLL followed by Ingenuity Pathway Analysis revealed that the most prominently regulated functions in TCL1 Tg vs non-transgenic (NTg) and TCL1 Tg vs PTPROt/TCL1 double Tg are the same and also biologically relevant to this study. Further, enhanced expression of the chemokine Ccl3, the oncogenic transcription factor Foxm1 and its targets in TCL1 Tg mice were significantly suppressed in the double Tg mice, suggesting a protective function of PTPROt against leukemogenesis. This study also showed that PTPROt-mediated regulation of Foxm1 involves activation of p53, a transcriptional repressor of Foxm1, which is facilitated through suppression of BCR signaling. These results establish the in vivo tumor-suppressive function of PTPROt and identify p53/Foxm1 axis as a key downstream effect of PTPROt-mediated suppression of BCR signaling.

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Acknowledgements

We thank the Ohio State University Comprehensive Cancer Center Microarray, Analytical Cytometry and Genetically Engineered Mouse Modeling Shared Resources for technical assistance. We thank Kalpana Ghoshal, Sarmila Majumder and Jharna Datta for valuable discussions; Satavisha Roy for experimental assistance; and Alexey Efanov for help with flow cytometry. This work was supported, in part, by the NIH grants CA101956 and CA086978 from the National Cancer Institute (to STJ).

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Authors and Affiliations

  1. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA

    T Motiwala, H Kutay & S T Jacob

  2. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA

    N Zanesi

  3. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    F W Frissora & S T Jacob

  4. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    X Mo

  5. Department of Internal Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    N Muthusamy

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  1. T Motiwala
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Correspondence to T Motiwala or S T Jacob.

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Motiwala, T., Kutay, H., Zanesi, N. et al. PTPROt-mediated regulation of p53/Foxm1 suppresses leukemic phenotype in a CLL mouse model. Leukemia 29, 1350–1359 (2015). https://doi.org/10.1038/leu.2014.341

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