title: Leukemogenesis caused by incapacitated GATA-1 function.
abstract: GATA-1 is essential for the development of erythroid and megakaryocytic lineages. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder resembling myelodysplastic syndrome that is characterized by the accumulation of progenitors expressing low levels of GATA-1. In this study, we demonstrate that GATA-1.05/X mice suffer from two distinct types of acute leukemia, an early-onset c-Kit-positive nonlymphoid leukemia and a late-onset B-lymphocytic leukemia. Since GATA-1 is an X chromosome gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the hematopoietic progenitors with the latter allele, low-level GATA-1 expression is sufficient to support survival and proliferation but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia has not been observed in GATA-1-null/X mutant mice, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. This de novo model recapitulates the acute crisis found in preleukemic conditions in humans.
authors.affiliation: Center for TARA, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Shimizu
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuroha
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohneda
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Pan
authors.forename: Kinuko
authors.initials: K
authors.lastname: Ohneda
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Sjaak
authors.initials: S
authors.lastname: Philipsen
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D005260:Female; D005434:Flow Cytometry; D050982:GATA1 Transcription Factor; D005803:Genes, Immunoglobulin; D016130:Immunophenotyping; D007938:Leukemia / Q000145:classification / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D008822:Mice, Transgenic; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism*; D014184:Transplantation, Homologous; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit