title: Physical association of the patient-specific GATA1 mutants with RUNX1 in acute megakaryoblastic leukemia accompanying Down syndrome.
abstract: Mutations of the GATA1 gene on chromosome X have been found in almost all cases of transient myeloproliferative disorder and acute megakaryoblastic leukemia (AMKL) accompanying Down syndrome (DS). Although most GATA1 mutations lead to the expression of GATA1s lacking the N-terminal activation domain, we recently found two novel GATA1 proteins with defects in another N-terminal region. It has been suggested that loss of the N-terminal portion of GATA1 might interfere with physiological interactions with the critical megakaryocytic transcription factor RUNX1, and this would imply that GATA1s is not able to interact properly with RUNX1. However, the interaction domain of GATA1 remains controversial. In this study, we show that GATA1 binds to RUNX1 through its zinc-finger domains, and that the C-finger is indispensable for synergy with RUNX1. All of the patient-specific GATA1 mutants interacted efficiently with RUNX1 and retained their ability to act synergistically with RUNX1 on the megakaryocytic GP1balpha promoter, whereas the levels of transcriptional activities were diverse among the mutants. Thus, our data indicate that physical interaction and synergy between GATA1 and RUNX1 are retained in DS-AMKL, although it is still possible that increased RUNX1 activity plays a role in the development of leukemia in DS.
authors.affiliation: 1Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.forename: R
authors.initials: R
authors.lastname: Kanezaki
authors.forename: T
authors.initials: T
authors.lastname: Toki
authors.forename: S
authors.initials: S
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Terui
authors.forename: I
authors.initials: I
authors.lastname: Kitabayashi
authors.forename: E
authors.initials: E
authors.lastname: Ito
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D002869:Chromosome Aberrations; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications* / Q000235:genetics*; D009154:Mutation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011784:Quail; D014158:Transcription, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D019038:Platelet Glycoprotein GPIb-IX Complex; C493728:RUNX1 protein, human