title: Murine Pten(-/-) T-ALL requires non-redundant PI3K/mTOR and DLL4/Notch1 signals for maintenance and γc/TCR signals for thymic exit.
abstract: T cell acute lymphoblastic leukemias (T-ALLs) commonly display constitutively active PI3K/mTOR and Notch signaling. However, controversy surrounds whether these pathways have independent functions and whether Pten loss is sufficient to generate resistance to Notch inhibition. Here we report that Pten(-/-) T-ALL is sensitive to either PI3K/mTOR or Notch inhibition alone, each pathway controlling distinct downstream signaling events that cannot be rescued by activation of the other pathway, consistent with independent, non-redundant functions. Although many human T-ALLs display constitutively activating Notch1 mutations, primary Pten(-/-) T-ALLs expressed wild-type Notch1 and depended on the Notch ligand DLL4 in vivo. Pten(-/-) T-ALLs with or without γc/TCR signaling responded similarly to PI3K/mTOR and Notch inhibition, although extended culture in vitro occasionally induced Notch-independent growth. However, unlike the T-ALLs lacking only Pten, eight of 23 Pten(-/-) T-ALLs that also lacked γc/TCR signaling accumulated Notch1 mutations, suggesting crosstalk between γc/TCR and Notch signaling. Importantly, we concluded that loss of γc/TCR signaling also inhibited thymic exit of Pten(-/-) T-ALLs. Our results may be clinically relevant in revealing that Pten loss is not sufficient to engender resistance to Notch inhibition, uncovering a role in T-ALL for ligand-dependent induction of wild-type Notch1, and suggesting that γc/TCR signaling could be targeted for preventing metastasis.
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Cell Biology and Histology, University of Amsterdam, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Immunology Discovery, Genentech Inc., South San Francisco, CA 94080, USA; Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, USA; Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: hagenbeek.thijs@gene.com.
authors.forename: Thijs J
authors.initials: TJ
authors.lastname: Hagenbeek
authors.affiliation: Department of Translational Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, USA; Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Choy
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Cheryll
authors.initials: C
authors.lastname: Sanchez-Irizarry
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.affiliation: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, USA; Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Siebel
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Cell Biology and Histology, University of Amsterdam, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; Department of Immunology Discovery, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: Hergen.Spits@amc.uva.nl.
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism* / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D053631:Interleukin Receptor Common gamma Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D058570:TOR Serine-Threonine Kinases; C519665:DLL4 protein, mouse; C497762:Notch1 protein, mouse; C546843:mTOR protein, mouse; C487757:Pten protein, mouse
keywords: Pten Notch1 T cell leukemia