Molecular and Cellular Biology, January 2000, p. 319-328, Vol. 20, No. 1
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Copyright © 2000, American Society for Microbiology. All rights reserved.


Departments of Hygiene,1 Internal Medicine,3 and Surgery,4 Kyoto Prefectural University of Medicine, Kyoto,5 and Department of Biochemistry, Hyogo Medical College, Nishinomiya,2 Japan, and Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee6
Received 6 July 1999/Returned for modification 9 August 1999/Accepted 5 October 1999
AML1 is one of the most frequently mutated genes
associated with human acute leukemia and encodes the DNA-binding
subunit of the heterodimering transcriptional factor complex,
core-binding factor (CBF) (or polyoma enhancer binding protein 2 [PEBP2]). A null mutation in either AML1 or its dimerizing partner,
CBF
, results in embryonic lethality secondary to a complete block in fetal liver hematopoiesis, indicating an essential role of this transcription complex in the development of definitive hematopoiesis. The hematopoietic phenotype that results from the loss of AML1 can be
replicated in vitro with a two-step culture system of murine embryonic
stem (ES) cells. Using this experimental system, we now demonstrate
that this hematopoietic defect can be rescued by expressing the
PEBP2
B1 (AML1b) isoform under the endogenous AML1-regulatory sequences through a knock-in (targeted
insertion) approach. Moreover, we demonstrate that the rescued
AML1
/
ES cell clones contribute to
lymphohematopoiesis within the context of chimeric animals. Rescue
requires the transcription activation domain of AML1 but does not
require the C-terminal VWRPY motif, which is conserved in all AML1
family members and has been shown to interact with the transcriptional
corepressor, Groucho/transducin-like Enhancer of split. Taken together,
these data provide compelling evidence that the phenotype seen in
AML1-deficient mice is due solely to the loss of
transcriptionally active AML1.
Present address: Research Institute for Microbial Diseases, Osaka
University, Suita, Japan.
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