PTEN is generally considered to be a tumor suppressor because it limits the activity of the PI3K-Akt pathway, which usually promotes cell survival. However, in pre-B cells transformed with BCR-ABL1 or NRASG12D, oncogenes common to acute lymphoblastic leukemia (ALL), Shojaee et al. found that deletion of Pten resulted in cell death, and mice transplanted with the transformed pre-B cells in which Pten was also deleted did not develop leukemia. Pten deletion in transformed pre-B cells resulted in increased phosphorylation of Akt, which is activated downstream of the pre-B cell receptor through the tyrosine kinase Syk. Pharmacological inhibition of Akt or Syk reduced cell death caused by Pten deletion; it also prevented the cell death of autoreactive B cells, which are eliminated through negative selection because the pre-BCR binds to self-antigen. Pten deletion did not affect the abundance of the tumor suppressor p53 or the survival of BCR-ABL1–transformed chronic myeloid leukemia (CML) cells. In contrast, Pten deletion in BCR-ABL1–transformed pre-B ALL cells triggered the phosphorylation of p53 and its accumulation, effects that required Akt activity. Overexpression of the myeloid transcription factor C/EBP-α converts cells of the B cell lineage to the myeloid lineage, and Pten deletion increased glycolysis to a greater extent in pre-B ALL cells than in myeloid-reprogrammed cells, as indicated by increased glucose consumption and lactate production and depletion of ATP. Analysis of a genetic database of human cancers indicated that PTEN deletions or point mutations were not detected in pre-B ALL patient samples, and PTEN abundance was increased in pre-B ALL patient samples compared to that in patient samples of other types of lymphomas and leukemias. PTEN knockdown reduced cell viability in four different patient-derived pre-B ALL cell lines, and pharmacological inhibition of PTEN increased AKT signaling; the phosphorylation and accumulation of p53; and glycolytic metabolism in human pre-B ALL cells. Thus, PTEN may be a potential therapeutic target for the treatment of pre-B ALL (see also Fortin et al.). S. Shojaee, L. N. Chan, M. Buchner, V. Cazzaniga, K. N. Cosgun, H. Geng, Y. H. Qiu, M. Dühren-von Minden, T. Ernst, A. Hochhaus, G. Cazzaniga, A. Melnick, S. M. Kornblau, T. G. Graeber, H. Wu, H. Jumaa, M. Müschen, PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat. Med. 22,379–387 (2016). [PubMed] J. Fortin, C. Bassi, T. W. Mak, PTEN enables the development of pre-B acute lymphoblastic leukemia. Nat. Med. 22, 339–340 (2016). [PubMed]
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