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The PTPROt tyrosine phosphatase functions as an obligate haploinsufficient tumor suppressor in vivo in B-cell chronic lymphocytic leukemia

Oncogene volume 36, pages 3686–3694 (2017)Cite this article

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Abstract

The tyrosine phosphatase PTPROt is a suggested tumor suppressor (TS) in B-cell chronic lymphocytic leukemia (CLL), and its expression is reduced in this disease. In order to examine how reduced PTPROt expression affects CLL in vivo we induced CLL in PTPROt-targeted mice. Unexpectedly, loss of both Ptprot alleles delayed disease detection and progression and lengthened survival relative to mice carrying two intact alleles, indicating that PTPROt fulfills a novel tumor-promoting role in CLL. Tumor cells from mice lacking PTPROt exhibited reduced B-cell receptor (BCR)-induced signaling, as well as increased apoptosis and autophagy. Inhibition of BCR/Src signaling in CLL cells induced their apoptosis, indicating that these findings are linked causally. These results suggest a cell-autonomous mechanism for the weakened CLL phenotype of PTPROt-deficient mice and uncover non-redundant roles for PTPROt in support of BCR signaling and survival of CLL cells. In contrast, loss of only one Ptprot allele induced earlier detection and progression of CLL and reduced survival, consistent with a tumor-suppressing role for PTPROt. Tumor cells from mice lacking one or both Ptprot allele exhibited increased interleukin-10 (IL-10) expression and signaling, factors known to support CLL; cells lacking one Ptprot alleles exhibited normal BCR signaling and cell death rates. We conclude that loss of one Ptprot allele promotes CLL, most likely by activating IL-10 signaling. Loss of both Ptprot alleles also reduces BCR signaling and increases cell death rates, offsetting the IL-10 effects and reducing the severity of the disease. PTPROt thus functions as an obligate haploinsufficient TS in CLL, where its expression levels determine its role as a promoter or inhibitor of the tumorigenic process in mice. Partial loss of PTPROt generates the strongest disease phenotype, suggesting that its intermediate expression levels in CLL are selected for.

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Acknowledgements

We thank Professor Carlo Croce for the Eμ-TCL1 mice, Professor Zvulun Elazar for the anti-LC3 antibodies, Dr Rebecca Haffner-Krausz for help in preparing PTPROt-targeted mice, Ms Ofira Higfa and Mr Neriah Sharabi for expert animal care, Dr Ron Rotkopf for help with statistical analyses, Dr Ayala Sharp and Mr Eitan Ariel for help with FACS analyses, and Dr Gil Hornung for assistance with analysis of IL-10 expression. JW is supported in part by a studentship from the German-Israeli Helmholtz Research School in Cancer Biology. This study was supported by project grants from the Israel Cancer Research Foundation, from the Minerva Foundation with funds from the Federal German Ministry for Education and Research, and from the Kekst Family Center for Medical Genetics, to AE. AE is the incumbent of the Marshall and Renette Ezralow Professorial Chair.

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Authors and Affiliations

  1. Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel

    J Wakim, E Arman & A Elson

  2. Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

    S Becker-Herman, M P Kramer, E Bakos & I Shachar

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Wakim, J., Arman, E., Becker-Herman, S. et al. The PTPROt tyrosine phosphatase functions as an obligate haploinsufficient tumor suppressor in vivo in B-cell chronic lymphocytic leukemia. Oncogene 36, 3686–3694 (2017). https://doi.org/10.1038/onc.2016.523

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