PTEN action in leukaemia dictated by the tissue microenvironment

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. (2014) PTEN action in leukaemia dictated by the tissue microenvironment. Nature, 510 (7505). p. 402. ISSN 0028-0836

URL: http://www.ncbi.nlm.nih.gov/pubmed/24805236
DOI: 10.1038/nature13239

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
CSHL Cancer Center Shared Resources > Instrumentation Service
CSHL Cancer Center Shared Resources > Next Generation Sequencing Service
CSHL labs > Hicks lab
CSHL labs > Lowe lab
Watson School > Publications
CSHL Cancer Center Shared Resources > Bioinformatics Service
Depositing User: Matt Covey
Date Deposited: 15 May 2014 18:46
Last Modified: 02 Nov 2015 17:36
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30141

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