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PTEN opposes negative selection and enables oncogenic transformation of pre-B cells

Nature Medicine volume 22, pages 379–387 (2016)Cite this article

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Abstract

Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre–B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL.

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Figure 1: Pten is required for leukemic transformation of pre-B cells.
Figure 2: Deletion of Pten compromises BCR-ABL1– and NRASG12D-driven leukemogenesis.
Figure 3: Pre-B ALL cells do not harbor genetic lesions in PTEN and do not tolerate hyperactivation of PI3K-AKT signaling.
Figure 4: Hyperactivation of AKT is a defining feature of autoreactive pre-BCR signaling and triggers a checkpoint for the removal of autoreactive pre-B cells.
Figure 5: Pre-B cell–specific functions of PTEN in normal progenitor cells and in leukemia.
Figure 6: A small-molecule inhibitor of PTEN is specifically toxic in pre-B ALL.

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Acknowledgements

We would like to thank L.M. Staudt (National Cancer Institute), D.A. Fruman (University of California, Irvine), T. Kurosaki (World Premier International (WPI) Immunology Frontier Research Center), S. Li (Dana-Farber Cancer Institute) and A. Weiss (University of California, San Francisco) for comments and critical discussion of this study. This work is supported by the US National Institutes of Health (NIH) and the National Cancer Institute through grants R01CA137060 (M.M.), R01CA139032 (M.M.), R01CA157644 (M.M.), R01CA169458 (M.M.) and R01CA172558 (M.M.), the William Lawrence and Blanche Hughes Foundation (M.M.), the California Institute for Regenerative Medicine (CIRM; grant TR2-01816; M.M.) and Bloodwise (M.M.). T.G.G. is the recipient of a Research Scholar Award from the American Cancer Society (award RSG-12-257-01-TBE), an Established Investigator Award from the Melanoma Research Alliance (award 20120279), and is supported by NIH–National Center for Advancing Translational Science (NCATS) UCLA CTSI grant UL1TR000124. M.M. is a Scholar of the Leukemia and Lymphoma Society and a Senior Investigator of the Wellcome Trust.

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Authors and Affiliations

  1. Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA

    Seyedmehdi Shojaee, Lai N Chan, Maike Buchner, Valeria Cazzaniga, Kadriye Nehir Cosgun, Huimin Geng & Markus Müschen

  2. Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy

    Valeria Cazzaniga & Giovanni Cazzaniga

  3. Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Yi Hua Qiu & Steven M Kornblau

  4. Department of Immunology, University of Ulm, Ulm, Germany

    Marcus Dühren von Minden & Hassan Jumaa

  5. Abteilung Hämatologie-Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    Thomas Ernst & Andreas Hochhaus

  6. Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA

    Ari Melnick

  7. Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), Los Angeles, California, USA

    Thomas G Graeber & Hong Wu

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Contributions

S.S. and M.M. designed experiments and interpreted data; M.M. conceived the study, obtained funding, coordinated collaborations and wrote the paper; S.S., L.N.C., M.B., V.C., K.N.C. and H.G. performed experiments and analyzed data; Y.H.Q., A.M. and S.M.K. provided and characterized patient samples or cell lines and clinical outcome data; H.W. provided important reagents and mouse samples; M.D.v.M., T.E., A.H., G.C., S.M.K., T.G.G. and H.J. provided conceptual input to the design of the study.

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Correspondence to Markus Müschen.

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Shojaee, S., Chan, L., Buchner, M. et al. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med 22, 379–387 (2016). https://doi.org/10.1038/nm.4062

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