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, Morimasa Wada

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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 mdr1 apromoter-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.

Original languageEnglish
Pages (from-to)759-766
Number of pages8
JournalBlood
Volume97
Issue number3
DOIs
Publication statusPublished - Feb 1 2001
Externally publishedYes

Fingerprint

MDR Genes
Terminal Repeat Sequences
Vincristine
Retroviridae
Transcriptional Activation
Leukemia
Genes
Chemical activation
5' Flanking Region
Polymerase chain reaction
Transcription
Genetic Promoter Regions
Cells
Up-Regulation
Experiments
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Retrovirus insertion and transcriptional activation of the multidrug-resistance gene in leukemias treated by a chemotherapeutic agent in vivo. / Nagayama, Jun; Iino, Mayumi; Tada, Yasuhiro; Kusaba, Hitoshi; Kiue, Akira; Ohshima, Koichi; Kuwano, Michihiko; Wada, Morimasa.

In: Blood, Vol. 97, No. 3, 01.02.2001, p. 759-766.

Research output: Contribution to journalArticle

Nagayama, Jun ; Iino, Mayumi ; Tada, Yasuhiro ; Kusaba, Hitoshi ; Kiue, Akira ; Ohshima, Koichi ; Kuwano, Michihiko ; Wada, Morimasa. / Retrovirus insertion and transcriptional activation of the multidrug-resistance gene in leukemias treated by a chemotherapeutic agent in vivo. In: Blood. 2001 ; Vol. 97, No. 3. pp. 759-766.
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abstract = "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 mdr1 apromoter-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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