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Blood, 1 February 2001, Vol. 97, No. 3, pp. 759-766
NEOPLASIA
Retrovirus insertion and transcriptional activation of the
multidrug-resistance gene in leukemias treated by a chemotherapeutic
agent in vivo
Jun Nagayama,
Mayumi Iino,
Yasuhiro Tada,
Hitoshi Kusaba,
Akira Kiue,
Koichi Ohshima,
Michihiko Kuwano, and
Morimasa Wada
From the Department of Medical Biochemistry, Graduate
School of Medical Sciences, Kyushu University, and the First Department
of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan,
and Nikken Chemicals Co Ltd, Oomiya Research Laboratory, Oomiya, Japan.
To understand the molecular basis for multidrug-resistant (MDR)
cancer cells in vivo, this study analyzed molecular changes of
the mdr1a gene region in leukemia cells in mice
during continuous treatment with vincristine. An inverse
insertion of murine leukemia retrovirus (MuLV) into the
5'-flanking region of the mdr1a gene was found.
This insertion was concomitantly accompanied by up-regulation of the
mdr1a gene and the loss of chemosensitivity. Deletion of long-terminal repeat (LTR) sequences dramatically decreased the mdr1a promoter-driven reporter activity. The MuLV LTR
insertion appears to exert its enhancer activity on
mdr1a transcription during the appearance of MDR leukemia
cells. Two mechanisms were postulated to explain the mdr1a
gene activation by retrovirus insertion during in vivo chemotreatment:
de novo insertion of MuLV induced by vincristine treatment and
selection of a small fraction of pre-existing cells carrying MuLV
insertion during vincristine treatment. No rearranged sequence was
detected by polymerase chain reaction in parental cells. This result
argued for the first mechanism. The randomly altered distribution of MuLV during repetitive chemotreatment might also be consistent with
this hypothesis. On the other hand, the retrovirus insertion was
detected at the same site of the mdr1a promoter region in 2 independent experiments, which suggests the second mechanism. It should
be noted that in vivo chemotreatment using vincristine could generate
the mdr1a-overexpressing cells through retrovirus insertion
and the enhancer effect of the LTR.
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