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J. Biol. Chem., Vol. 281, Issue 48, 36501-36509, December 1, 2006

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Characterization of Gene Rearrangements Leading to Activation of MDR-1^*>

Lyn M. Huff, Jong-Seok Lee, Robert W. Robey, and Tito Fojo¹

From the Medical Oncology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and Seoul National University, Bandung Hospital, Seoul 151-742, South Korea

Expression of the MDR-1/P-glycoprotein gene confers drug resistance both in vitro and in vivo. We previously reported that gene rearrangements resulting in a hybrid MDR-1 transcript represent a common mechanism for acquired activation of MDR-1/P-glycoprotein. We have identified hybrid MDR-1 transcripts in nine MDR-1-overexpressing cell lines and two patients with relapsed ALL. We characterize these rearrangements as follows. 1) Non-MDR-1 sequences in the hybrid MDR-1 transcripts are expressed in unselected cell lines, showing that these sequences are constitutively expressed. 2) The rearrangements occur randomly and involve partner genes (sequences) on chromosome 7 and on chromosomes other than 7. Breakpoints have been characterized in six cell lines. In one, the rearrangement occurred within intron 2 of MDR-1; in the other five, the rearrangement occurred 24 to >96 kb 5' of the normal start of transcription of MDR-1. In one cell line, homologous recombination involving an Alu repeat was observed. However, in the remaining five cell lines, nonhomologous recombination was observed. 3) The rearrangements arise during drug selection. The acquired rearrangements are not detected in parental cells. 4) Five of the six active promoters that captured MDR-1 controlled MDR-1 from a distance of 29 to more than 110 kb 5' to MDR-1. Transcription was initiated in an antegrade or retrograde direction. We conclude that drug selection with natural products targeting DNA or microtubules leads to DNA damage, nonhomologous recombination, and acquired drug resistance, wherein MDR-1 expression is driven by a random but constitutively active promoter.

Received for publication, March 29, 2006 , and in revised form, June 7, 2006.

Note Added in Proof—HSCARG has been renamed NMRAL-1 (NmrA-like family domain-containing 1 gene; Gene ID: 57407) since the original submission of the manuscript.

^* This work was supported by the Intramural Research Program of NCI, National Institutes of Health, Center for Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1–3.

¹ A Commissioned Officer in the United States Public Health Service. To whom correspondence should be addressed: NCI, National Institutes of Health, Center for Cancer Research, Medical Oncology Branch, Bldg. 10, Rm. 12N226, 9000 Rockville Pike, Bethesda, MD 20892. Tel.: 301-402-1357; Fax: 301-402-1608; E-mail: tfojo{at}helix.nih.gov.

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