Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors

Tsukasa Okuda, Zhongling Cai, Shouli Yang, Noel Lenny, Chuhl Joo Lyu, Jan Van Deursen, Hironori Harada, James R. Downing

Research output: Contribution to journalArticle

300 Citations (Scopus)

Abstract

The t(8;21)-encoded AML1-ETO chimeric product is believed to be causally involved in up to 15% of acute myelogenous leukemias through an as yet unknown mechanism. To directly investigate the role of AML1-ETO in leukemogenesis, we used gene targeting to create an AML1-ETO 'knock-in' allele that mimics the t(8;21). Unexpectedly, embryos heterozygous for AML1- ETO (AML1-ETO/+) died around E13.5 from a complete absence of normal fetal liver-derived definitive hematopoiesis and lethal hemorrhages. This phenotype was similar to that seen following homozygous disruption of either AML1 or CBFβ. However, in contrast to AML1- or CBFβ-deficient embryos, fetal livers from AML1-ETO/+ embryos contained dysplastic multilineage hematopoietic progenitors that had an abnormally high self-renewal capacity in vitro. To further document the role of AML1-ETO in these growth abnormalities, we used retroviral transduction to express AML1-ETO in murine adult bone marrow- derived hematopoietic progenitors AML1-ETO-expressing cells were again found to have an increased self-renewal capacity and could be readily established into immortalized cell lines in vitro. Taken together, these studies suggest that AML1-ETO not only neutralizes the normal biologic activity of AML1 but also directly induces aberrant hematopoietic cell proliferation.

Original languageEnglish (US)
Pages (from-to)3134-3143
Number of pages10
JournalBlood
Volume91
Issue number9
StatePublished - May 1 1998
Externally publishedYes

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Hematopoiesis
Liver
Leukemia
Embryonic Structures
Genes
Cell proliferation
Bone
Gene Targeting
Cells
Acute Myeloid Leukemia
Bone Marrow
Alleles
Cell Proliferation
Hemorrhage
Phenotype
Cell Line
Growth
In Vitro Techniques

ASJC Scopus subject areas

  • Hematology

Cite this

Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. / Okuda, Tsukasa; Cai, Zhongling; Yang, Shouli; Lenny, Noel; Lyu, Chuhl Joo; Van Deursen, Jan; Harada, Hironori; Downing, James R.

In: Blood, Vol. 91, No. 9, 01.05.1998, p. 3134-3143.

Research output: Contribution to journalArticle

Okuda, Tsukasa ; Cai, Zhongling ; Yang, Shouli ; Lenny, Noel ; Lyu, Chuhl Joo ; Van Deursen, Jan ; Harada, Hironori ; Downing, James R. / Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. In: Blood. 1998 ; Vol. 91, No. 9. pp. 3134-3143.
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