title: Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome.
abstract: Children with Down syndrome have an increased incidence of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia. The majority of these cases harbor somatic mutations in the GATA1 gene, which results in the loss of full-length GATA1. Only a truncated isoform of GATA1 that lacks the N-terminal 83 amino acids (GATA1-S) remains. We found through genetic studies of 106 patients with TAM that internally deleted GATA1 proteins (GATA1-IDs) lacking amino acid residues 77-119 or 74-88 (created by splicing mutations) contributed to the genesis of TAM in 6 patients. Analyses of GATA1-deficient embryonic megakaryocytic progenitors revealed that the GATA1 function in growth restriction was disrupted in GATA1-IDs. In contrast, GATA1-S promoted megakaryocyte proliferation more profoundly than that induced by GATA1 deficiency. These results indicate that the internally deleted regions play important roles in megakaryocyte proliferation and that perturbation of this mechanism is involved in the pathogenesis of TAM.
authors: Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
authors: Tsutomu
authors: T
authors: Toki
authors: Rika
authors: R
authors: Kanezaki
authors: Eri
authors: E
authors: Kobayashi
authors: Hiroshi
authors: H
authors: Kaneko
authors: Mikiko
authors: M
authors: Suzuki
authors: Runan
authors: R
authors: Wang
authors: Kiminori
authors: K
authors: Terui
authors: Hirokazu
authors: H
authors: Kanegane
authors: Miho
authors: M
authors: Maeda
authors: Mikiya
authors: M
authors: Endo
authors: Tatsuki
authors: T
authors: Mizuochi
authors: Souichi
authors: S
authors: Adachi
authors: Yasuhide
authors: Y
authors: Hayashi
authors: Masayuki
authors: M
authors: Yamamoto
authors: Ritsuko
authors: R
authors: Shimizu
authors: Etsuro
authors: E
authors: Ito
mesh_terms: D049109:Cell Proliferation; D002648:Child; D004314:Down Syndrome / Q000097:blood* / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D050982:GATA1 Transcription Factor / Q000235:genetics*; D006801:Humans; D007955:Leukemoid Reaction / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion
chemical_list: D050982:GATA1 Transcription Factor