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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 M.A. van Deursen,
Hironori Harada, and
James R. Downing
From the Departments of Pathology and Laboratory Medicine, Tumor Cell
Biology, and Genetics, St Jude Children's Research Hospital, Memphis,
TN.
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
CBF . However, in contrast to AML1- or
CBF-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.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3134-3143
© 1998 by The American Society of Hematology.
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