title: Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia.
abstract: Trib1 has been identified as a myeloid oncogene in a murine leukemia model. Here we identified a TRIB1 somatic mutation in a human case of Down syndrome-related acute megakaryocytic leukemia. The mutation was observed at well-conserved arginine 107 residue in the pseudokinase domain. This R107L mutation remained in leukocytes of the remission stage in which GATA1 mutation disappeared, suggesting the TRIB1 mutation is an earlier genetic event in leukemogenesis. The bone marrow transfer experiment showed that acute myeloid leukemia development was accelerated by transducing murine bone marrow cells with the R107L mutant in which enhancement of ERK phosphorylation and C/EBPα degradation by Trib1 expression was even greater than in those expressing wild-type. These results suggest that TRIB1 may be a novel important oncogene for Down syndrome-related acute megakaryocytic leukemia.
authors.affiliation: Division of Carcinogenesis, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Aoki
authors.forename: Rika
authors.initials: R
authors.lastname: Kanezaki
authors.forename: Myoung-Ja
authors.initials: MJ
authors.lastname: Park
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kanno
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takahara
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007947:Leukemia, Megakaryoblastic, Acute / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C493170:TRIB1 protein, human; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases