Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer

Junko Mitsuhashi, Satomi Tsukahara, Rieko Suzuki, Yumiko Oh-Hara, Saori Nishi, Hiroyo Hosoyama, Kazuhiro Katayama, Kohji Noguchi, Sayuri Minowa, Harumi Shibata, Yoshinori Ito, Kiyohiko Hatake, Keisuke Aiba, Shunji Takahashi, Yoshikazu Sugimoto

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Abstract

A clinical study of an MDR1 gene therapy protocol targeting metastatic breast cancer has been conducted in which the patients received high-dose chemotherapy, a transplant of MDR1-transduced autologous CD34+ cells, and docetaxel. We herein report the molecular results of a 6-year follow-up of an individual in this study (patient 1). HaMDR-transduced cells, which had been initially detected in the peripheral blood of this individual, were found to have gradually decreased. After 10 cycles of docetaxel (days 71-316), MDR1 transgene levels were found to have increased, and then decreased to undetectable levels by day 1461. Thirty-eight MDR1-transduced clones were identified in patient 1, of which 11 showed a retroviral integration in close proximity to genes listed in the Retrovirus Tagged Cancer Gene Database (RTCGD). Four short-life clones in this group were found to harbor retroviral integrations close to the ZFHX1B, NOTCH1, BMI1, or HHEX gene; these genes have been frequently reported in the RTCGD. In addition, a long-lived RTCGD-hit clone, L-34, had a retroviral integration at a position 179 kb upstream of the EVI1 gene. L-34 was detectable on days 327-1154, but became undetectable 3 years after the docetaxel treatments had ceased. An additional three docetaxel-induced long-life clones showed comparable polymerase chain reaction profiles, which were also similar to that of the total MDR1-transduced cells. Our results thus show that docetaxel may have been effective in promoting the expansion of several MDR1-transduced clones in patient 1, but that they persist in the peripheral blood for only a few years.

Original languageEnglish
Pages (from-to)895-906
Number of pages12
JournalHuman Gene Therapy
Volume18
Issue number10
DOIs
Publication statusPublished - 2007 Oct 1

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Mitsuhashi, J., Tsukahara, S., Suzuki, R., Oh-Hara, Y., Nishi, S., Hosoyama, H., Katayama, K., Noguchi, K., Minowa, S., Shibata, H., Ito, Y., Hatake, K., Aiba, K., Takahashi, S., & Sugimoto, Y. (2007). Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer. Human Gene Therapy, 18(10), 895-906. https://doi.org/10.1089/hum.2007.075