Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome

Tsutomu Toki, Rika Kanezaki, Eri Kobayashi, Hiroshi Kaneko, Mikiko Suzuki, Ru Nan Wang, Kiminori Terui, Hirokazu Kanegane, Miho Maeda, Mikiya Endo, Tatsuki Mizuochi, Souichi Adachi, Yasuhide Hayashi, Masayuki Yamamoto, Ritsuko Shimizu, Etsuro Ito

研究成果: Article

18 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)3181-3184
ページ数4
ジャーナルBlood
121
16
DOI
出版ステータスPublished - 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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