Leukemogenesis caused by incapacitated GATA-1 function

Ritsuko Shimizu, Takashi Kuroha, Osamu Ohneda, Xiaoqing Pan, Kinuko Ohneda, Satoru Takahashi, Sjaak Philipsen, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10814-10825
Number of pages12
JournalMolecular and cellular biology
Volume24
Issue number24
DOIs
Publication statusPublished - 2004 Dec
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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