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.
authors.affiliation: 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Department of Medicine I, Medical Center - University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Miething
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Scuoppo
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bosbach
authors.affiliation: 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Appelmann
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Nakitandwe
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Howard Hughes Medical Institute, New York, New York 10065, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Lintault
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Auer
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Prem K
authors.initials: PK
authors.lastname: Premsrirut
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Departments of Anesthesiology and Radiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Benveniste
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Howard Hughes Medical Institute, New York, New York 10065, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D018925:Chemokines; D043562:Receptors, G-Protein-Coupled; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse