PTEN action in leukaemia dictated by the tissue microenvironment Journal Article

Authors: Miething, C.; Scuoppo, C.; Bosbach, B.; Appelmann, I.; Nakitandwe, J.; Ma, J.; Wu, G.; Lintault, L.; Auer, M.; Premsrirut, P. K.; Teruya-Feldstein, J.; Hicks, J.; Benveniste, H.; Speicher, M. R.; Downing, J. R.; Lowe, S. W.
Article Title: PTEN action in leukaemia dictated by the tissue microenvironment
Abstract: PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype. © 2014 Macmillan Publishers Limited. All rights reserved.
Keywords: immunohistochemistry; signal transduction; protein kinase b; cancer survival; controlled study; leukemia; unclassified drug; gene mutation; nonhuman; flow cytometry; nuclear magnetic resonance imaging; positron emission tomography; cd8+ t lymphocyte; animal cell; mouse; animals; cell survival; gene overexpression; apoptosis; gene expression; spleen; embryo; lipid; animal experiment; animal model; genotype; rna interference; cell differentiation; enzyme activity; acute lymphoblastic leukemia; mus musculus; mice, transgenic; survival time; liver; enzyme phosphorylation; gene rearrangement; chemokine; leukemia cell; lymph node; cd4+ t lymphocyte; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; fluorodeoxyglucose f 18; immunoblotting; cell migration; fibroblast; epithelium cell; upregulation; rodent; gene silencing; cyclin dependent kinase inhibitor 2a; tumor growth; tumor; rag1 protein; doxycycline; chemokine receptor ccr7; comparative genomic hybridization; phosphate; receptors, g-protein-coupled; thymocyte; intestine; short hairpin rna; gene knockdown techniques; chemokines; cell homing; notch1 receptor; enhanced green fluorescent protein; heterogeneity; tumor microenvironment; spectral karyotyping; chemokine receptor ccr9; phosphatidylinositol 3-kinases; protein s6; thymus hyperplasia; blood system disorder; leukemic infiltration; t lymphocyte receptor gene; genetic difference; cancer; priority journal; article; ccl25 chemokine
Journal Title: Nature
Volume: 510
Issue: 7505
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2014-06-19
Start Page: 402
End Page: 406
Language: English
DOI: 10.1038/nature13239
PUBMED: 24805236
PROVIDER: scopus
PMCID: PMC4165899
Notes: Cited By (since 1996):1 -- Export Date: 1 August 2014 -- CODEN: NATUA -- Source: Scopus
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MSK Authors
  1. Julie T Feldstein
    288 Feldstein
  2. Scott W Lowe
    145 Lowe