title: A PI3K p110β-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis.
abstract: The tumour suppressor PTEN, which antagonizes PI3K signalling, is frequently inactivated in haematologic malignancies. In mice, deletion of PTEN in haematopoietic stem cells (HSCs) causes perturbed haematopoiesis, myeloproliferative neoplasia (MPN) and leukaemia. Although the roles of the PI3K isoforms have been studied in PTEN-deficient tumours, their individual roles in PTEN-deficient HSCs are unknown. Here we show that when we delete PTEN in HSCs using the Mx1-Cre system, p110β ablation prevents MPN, improves HSC function and suppresses leukaemia initiation. Pharmacologic inhibition of p110β in PTEN-deficient mice recapitulates these genetic findings, but suggests involvement of both Akt-dependent and -independent pathways. Further investigation reveals that a p110β-Rac signalling loop plays a critical role in PTEN-deficient HSCs. Together, these data suggest that myeloid neoplasia driven by PTEN loss is dependent on p110β via p110β-Rac-positive-feedback loop, and that disruption of this loop may offer a new and effective therapeutic strategy for PTEN-deficient leukaemia.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Haluk
authors.initials: H
authors.lastname: Yuzugullu
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Baitsch
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Thanh
authors.initials: T
authors.lastname: Von
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Steiner
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Haoxuan
authors.initials: H
authors.lastname: Tong
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ni
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Clayton
authors.affiliation: Dana-Farber/Harvard Cancer Center Rodent Histopathology Core, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Roberts
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Kira
authors.initials: K
authors.lastname: Gritsman
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D002633:Chemotaxis; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D009196:Myeloproliferative Disorders / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D020744:rac GTP-Binding Proteins
chemical_list: C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020744:rac GTP-Binding Proteins