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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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Shojaee S,Chan LN,Buchner M,Cazzaniga V,Cosgun KN,Geng H,Qiu YH,von Minden MD,Ernst T,Hochhaus A,Cazzaniga G,Melnick A,Kornblau SM,Graeber TG,Wu H,Jumaa H,Müschen M

doi

10.1038/nm.4062

subject

Has Abstract

pub_date

2016-04-01 00:00:00

pages

379-87

issue

4

eissn

1078-8956

issn

1546-170X

pii

nm.4062

journal_volume

22

pub_type

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