title: TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia.
abstract: The presence of AML1-ETO (RUNX1-CBF2T1), a fusion oncoprotein resulting from a t(8;21) chromosomal translocation, has been implicated as a necessary but insufficient event in the development of a subset of acute myeloid leukemias (AML). While AML1-ETO prolongs survival and inhibits differentiation of hematopoietic stem cells (HSC), other contributory events are needed for cell proliferation and leukemogenesis. We have postulated that specific tumor suppressor genes keep the leukemic potential of AML1-ETO in check. In studying del(9q), one of the most common concomitant chromosomal abnormalities with t(8;21), we identified the loss of an apparent tumor suppressor, TLE4, that appears to cooperate with AML1-ETO to confer a leukemic phenotype. This study sought to identify the molecular basis of this cooperation. We show that the loss of TLE4 confers proliferative advantage to leukemic cells, simultaneous with an upregulation of a pro- inflammatory signature mediated through aberrant increases in Wnt signaling activity. We further demonstrate that inhibition of cyclooxygenase (COX) activity partly reverses the pro-leukemic phenotype due to TLE4 knockdown, pointing towards a novel therapeutic approach for myeloid leukemia.
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, MA 02114, United States; Department of Molecular and Translational Medicine, Boston University School of Medicine, Boston, MA 02118, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Shin
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brynczka
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: Farshid
authors.initials: F
authors.lastname: Dayyani
authors.affiliation: Department of Pathology, Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA 02129, United States.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, MA 02114, United States. Electronic address: dsweetser@partners.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Sweetser
mesh_terms: D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007249:Inflammation; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D009687:Nuclear Proteins; D012097:Repressor Proteins; C465817:TLE4 protein, human; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins
keywords: AML1-ETO; Acute myeloid leukemia; Inflammation; TLE4; Tumor suppressor; Wnt signaling