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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1144-1150
PLENARY PAPER
Acquired loss of p53 induces blastic transformation in
p210bcr/abl-expressing hematopoietic cells: a
transgenic study for blast crisis of human CML
Hiroaki Honda,
Toshikazu Ushijima,
Kuniko Wakazono,
Hideaki Oda,
Yuji Tanaka,
Shin-ichi Aizawa,
Takatoshi Ishikawa,
Yoshio Yazaki, and
Hisamaru Hirai
From the Third Department of Internal Medicine, Faculty of Medicine,
University of Tokyo, Tokyo, Japan; Carcinogenesis Division, National
Cancer Center Research Institute, Tokyo, Japan; the Department of
Pathology, University of Tokyo, Japan; and the Department of
Morphogenesis, Institute of Molecular Embryology and Genetics, Kumamoto
University School of Medicine, Kumamoto, Japan.
Chronic myelogenous leukemia (CML) begins with an indolent chronic
phase but inevitably progresses to a fatal blast crisis. Although the
Philadelphia chromosome, which generates
p210bcr/abl, is a unique chromosomal abnormality in
the chronic phase, additional chromosomal abnormalities are frequently
detected in the blast crisis, suggesting that superimposed genetic
events are responsible for disease progression. To investigate whether
loss of p53 plays a role in the evolution of CML, we crossmated
p210bcr/abl-transgenic
(BCR/ABLtg/ ) mice with p53-heterozygous
(p53+/) mice and generated
p210bcr/abl-transgenic, p53-heterozygous
(BCR/ABLtg/p53+/)
mice, in which a somatic alteration in the residual normal p53 allele directly abrogates p53 function. The
BCR/ABLtg/p53+/ mice
died in a short period compared with their wild-type
(BCR/ABL/p53+/+),
p53 heterozygous
(BCR/ABL/p53+/),
and p210bcr/abl transgenic
(BCR/ABLtg/p53+/+)
litter mates. They had rapid proliferation of blast cells, which was preceded by subclinical or clinical signs of a myeloproliferative disorder resembling human CML. The blast cells were clonal in origin and expressed p210bcr/abl with an
increased kinase activity. Interestingly, the residual normal p53
allele was frequently and preferentially lost in the tumor tissues,
implying that a certain mechanism facilitating the loss of p53 allele
exists in p210bcr/abl-expressing hematopoietic
cells. Our study presents in vivo evidence that acquired loss of p53
contributes to the blastic transformation of
p210bcr/abl-expressing hematopoietic cells and
provides insights into the molecular mechanism for blast crisis of
human CML.
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