UCSF UC San Francisco Previously Published Works

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

Permalink https://escholarship.org/uc/item/50p8r92k

Journal Nature medicine, 22(4)

ISSN 1078-8956

Authors Shojaee, Seyedmehdi Chan, Lai N Buchner, Maike et al.

Publication Date 2016-04-01

DOI 10.1038/nm.4062

Peer reviewed

eScholarship.org Powered by the California Digital Library University of California © 2016 Nature America, Inc. All rights reserved. (UCLA), Los Angeles, California, USA. Correspondence should be addressed to M.M. ( Pharmacology, Weill Cornell Medical College, New York, New York, USA. University of Ulm, Ulm, Germany. di Milano-Bicocca, Monza, Italy. 1 phosphorylates which PI3K, that of (PIP (4,5)-bisphosphate phosphatase activity phosphatidylinositol the lipid and counteracts PTEN protein (PIP dual (3,4,5)-triphosphate a phosphatidylinositol dephosphorylates as functions and signaling. of PI3K level for an intermediate selection undergo effects on human early B deleterious cell developmentequally have signaling loss PI3K-AKT of either in hyperactivation or result that humans in mutations germline Likewise, BCR of a functional absence tion of PI3K-AKT signaling is sufficient to rescue B cell survival in the owing to the toxicity of strong pre-BCR eliminated signaling are clones cell pre-B autoreactive Although checkpoint. pre-BCR the at clones autoreactive of selection negative stringent of autoreactive an express cells B pre- generated Approximately of newly 75% death. cell and selection autoreactive pre-BCR) threshold of signaling strength trigger negative an as (such maximum a above hyperactivation and pre-BCR) tional nonfunc a as (such minimum a below attenuation Both strong. are reactive immunoglobulin (auto self-antigen ubiquitous to binds pre-BCR the If weak. too is output cell clones then signaling fail to pre-BCR, express a functional pre-B if pre-BCR; the from come signals proliferation and survival checkpoint at (pre-BCR) receptor pre–B the eliminated cell are marrow bone the in cells pre-B generated newly of majority The strategy to overcome drug resistance in human ALL. of PTEN and of hyperactivation AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre–B cell receptor pre-B ALL cells resulted in of hyperactivation AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. inhibition Small-molecule of PTEN in human In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of PTEN in pre-B acute leukemia lymphoblastic (ALL), we induced Cre-mediated deletion of kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for Phosphatase and tensin homolog (PTEN) is a negative regulator of the 3-kinase (PI3K) phosphatidylinositol and protein Ari Melnick Yi Hua Qiu Seyedmehdi Shojaee transformation of pre-B cells PTEN nature medicine nature Received 11 June 2015; accepted 10 February 2016; published online 14 March 2016; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA. PTEN is a key negative regulator of the PI3K-AKT pathway pathway PI3K-AKT the of regulator negative key a is PTEN 3 opposes negative and selection enables oncogenic 6 , , Marcus Dühren von Minden , , Steven M Kornblau

advance online publication online advance 1 µ , Lai N Chan heavy chain; 3 4 Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. 5 and is required for pre-B cell survival for cell pre-B required is and Abteilung Hämatologie-Onkologie, Klinik für