title: Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo.
abstract: P38α/β has been described as a tumor-suppressor controlling cell cycle checkpoints and senescence in epithelial malignancies. However, p38α/β also regulates other cellular processes. Here, we describe a role of p38α/β as a regulator of acute lymphoblastic leukemia (ALL) proliferation and survival in experimental ALL models. We also report first evidence that p38α/β phosphorylation is associated with the occurrence of relapses in TEL-AML1-positive leukemia. First, in vitro experiments show that p38α/β signaling is induced in a cyclical manner upon initiation of proliferation and remains activated during log-phase of cell growth. Next, we provide evidence that growth-permissive signals in the bone marrow activate p38α/β in a novel avian ALL model, in which therapeutic targeting can be tested. We further demonstrate that p38α/β inhibition by small molecules can suppress leukemic expansion and prolong survival of mice bearing ALL cell lines and primary cells. Knockdown of p38α strongly delays leukemogenesis in mice xenografted with cell lines. Finally, we show that in xenografted TEL-AML1 patients, ex vivo p38α/β phosphorylation is associated with an inferior long-term relapse-free survival. We propose p38α/β as a mediator of proliferation and survival in ALL and show first preclinical evidence for p38α/β inhibition as an adjunct approach to conventional therapies.
authors.affiliation: Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Alsadeq
authors.affiliation: Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Strube
authors.affiliation: Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Krause
authors.affiliation: Helmholtz Zentrum München, Department of Gene Vectors, Research Center for Environmental Health, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Carlet
authors.affiliation: Helmholtz Zentrum München, Department of Gene Vectors, Research Center for Environmental Health, Munich, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Jeremias
authors.affiliation: Kiel Pediatric Tumor Registry, Department of Pediatric Pathology, University of Kiel, Kiel, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Vokuhl
authors.affiliation: II. Medical Clinic and Institute of Tumor Biology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Loges
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.|Department of Otolaryngology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Trauzold
authors.affiliation: Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Cario
authors.affiliation: Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: D M
authors.initials: DM
authors.lastname: Schewe
mesh_terms: D000293:Adolescent; D000818:Animals; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases