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

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.

SUBMITTER: Shojaee S

PROVIDER: S-EPMC5178869 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Shojaee Seyedmehdi S Chan Lai N LN Buchner Maike M Cazzaniga Valeria V Cosgun Kadriye Nehir KN Geng Huimin H Qiu Yi Hua YH von Minden Marcus Dühren MD Ernst Thomas T Hochhaus Andreas A Cazzaniga Giovanni G Melnick Ari A Kornblau Steven M SM Graeber Thomas G TG Wu Hong H Jumaa Hassan H Müschen Markus M

Nature medicine 20160314 4

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 ...[more]

PMID: 26974310

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Project description:Targeted therapy of cancer typically focuses on the development of agents that will inactivate a transforming oncogene. In this study, we tested the concept that besides the oncogene itself, factors that enable permissiveness of a normal cell to oncogenic signaling represent a novel class of therapeutic targets. This hypothesis was based on our finding that acute activation of oncogenes in normal pre-B cells typically results in immediate cell death, unless pre-B cells were capable of adapting quickly enough to a high level of signaling output in Erk and Stat5 pathways. Surviving pre-B cell clones achieved permissiveness to oncogenic signaling by strong upregulation of negative feedback regulators of Erk (DUSP6, SPRY2, ETV5) and Stat5 (CISH, SOCS2, SOCS3) signaling. Genetic deletion of the sprouty family Ras inhibitor Spry2, the Erk phosphatase Dusp6 or Etv5, a transcriptional activator of SPRY2/DUSP6, decreased robustness of negative feedback control and compromised oncogenic transformation. Likewise, ablation of the suppressors of cytokine signaling (SOCS) family molecules Cish, Socs2 and Socs3 reversed permissiveness of pre-B cells to oncogenic signaling. Searching for factors that limit permissiveness of normal pre-B cells to oncogene signaling, we identified the lymphoid transcription factor IKZF1, which functions as a critical tumor suppressor in pre-B ALL. IKZF1 binds directly to and transcriptionally represses DUSP6, SPRY2, ETV5, CISH, SOCS2, and SOCS3 promoters, hence lowering the threshold of maximum allowable oncogene signaling strength. Interstingly, a small molecule inhibitor of DUSP6 acutely subverted negative feedback regulation and selectively induced cell death in pre-B ALL cells. In addition, small molecule inhibition of DUSP6 was sufficient to overcome conventional mechanisms of drug-resistance in pre-B ALL and had strong selective activity on drug-resistant patient-derived pre-B ALL cells that were injected into NOD/SCID transplant recipient mice. These findings identify permissive negative feedback control of oncogenic signaling as a previously unrecognized vulnerability of pre-B ALL cells and a new class of potential therapeutic targets.

Dataset Information

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

Publications

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

Similar Datasets

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