title: Induction of hyperproliferative fetal megakaryopoiesis by an N-terminally truncated GATA1 mutant.
abstract: Two GATA1-related leukemias have been described: one is an erythroleukemia that develops in mice as a consequence of diminished expression of wild-type GATA1, whereas the other is an acute megakaryoblastic leukemia (AMKL) that arises in Down syndrome children as a consequence of somatic N-terminal truncation (DeltaNT) of GATA1. We discovered that mice expressing the shortened GATA1 protein (DeltaNTR mice) phenocopies the human transient myeloproliferative disorder (TMD) that precedes AMKL in Down syndrome children. In perinatal livers of the DeltaNTR mutant mice, immature megakaryocytes accumulate massively, and this fraction contains cells that form hyperproliferative megakaryocytic colonies. Furthermore, showing good agreement with the clinical course of TMD in humans, DeltaNTR mutant mice undergo spontaneous resolution from the massive megakaryocyte accumulation concomitant with the switch of hematopoietic microenvironment from liver to bone marrow/spleen. These results thus demonstrate that expression of the GATA1/Gata1 N-terminal deletion mutant per se induces hyperproliferative fetal megakaryopoiesis. This mouse model serves as an important means to clarify how impaired GATA1 function contributes to the multi-step leukemogenesis.
authors.affiliation: Department of Experimental Hematology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Shimizu
authors.forename: Eri
authors.initials: E
authors.lastname: Kobayashi
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001853:Bone Marrow; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000503:physiopathology; D004622:Embryo, Mammalian; D005260:Female; D005315:Fetal Diseases / Q000235:genetics / Q000503:physiopathology; D050982:GATA1 Transcription Factor / Q000235:genetics*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics / Q000503:physiopathology; D008533:Megakaryocytes / Q000166:cytology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000503:physiopathology
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human