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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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.
The authors declare no competing financial interests.
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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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