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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3154-3160
NEOPLASIA
Mutations of the AML1 gene in
myelodysplastic syndrome and their functional implications in
leukemogenesis
Yoichi Imai,
Mineo Kurokawa,
Koji Izutsu,
Akira Hangaishi,
Kengo Takeuchi,
Kazuhiro Maki,
Seishi Ogawa,
Shigeru Chiba,
Kinuko Mitani, and
Hisamaru Hirai
From the Department of Hematology and Oncology and the
Department of Pathology, Graduate School of Medicine, University of
Tokyo, Tokyo, Japan.
The AML1 gene encodes a DNA-binding protein that
contains the runt domain and is the most frequent target of
translocations associated with human leukemias. Here, point mutations
of the AML1 gene, V105ter (single-letter amino acid
code) and R139G, (single-letter amino acid codes)
were identified in 2 cases of myelodysplastic syndrome (MDS) by means
of the reverse transcriptase-polymerase chain reaction single-strand
conformation polymorphism method. Both mutations are present in the
region encoding the runt domain of AML1 and cause
loss of the DNA-binding ability of the resultant products. Of these
mutants, V105ter has also lost the ability to heterodimerize with
polyomavirus enhancer binding protein 2/core binding factor  (PEBP2/CBF). On the other hand, the R139G mutant acts as a
dominant negative inhibitor by competing with wild-type AML1 for
interaction with PEBP2/CBF. This study is the first report that
describes mutations of AML1 in patients with MDS
and the mechanism whereby the mutant acts as a dominant negative
inhibitor of wild-type AML1.
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