Genomic gain and loss associated with drug-resistance of CCRF-CEM leukemic cells

T Efferth, PhD, a, I Verdorfer, PhD, A Sauerbrey, MD, H Miyachi, PhD, CR Chitambar, PhD, HG Drexler PhD, and E Gebhart, PhD

a Virtual Campus Rhineland-Palatinate, Rodeneck-Platz 2, 55126 Mainz, Germany; e-mail:

Aim: We analyzed genomic imbalances associated with resistance to cytostatic drug resistance in 10 CCRF-CEM cell lines resistant to either methotrexate (MTX), doxorubicin (DOX), vincristine (VCR), or hydroxyurea (HUR) in comparison to parental, drug-sensitive cells. Methods: Gain and loss of genomic DNA were analyzed using comparative genomic hybridization. Evaluation was done by CGH software ISIS3 (Metasystems, Altlussheim, Germany). Results: Loss of distal bands of chromosome 9p was shared by all sensitive and resistant CCRF-CEM lines. Enhancement (enh) or amplification (amp) of 5q13q14 was found in 7/7, enh 14q21qter in 4/7, and enh 17q21qter in 3/7 MTX-resistant CEM lines. Enh 7p21pter and enh 13q14qter were found in DOX- and VCR-resistant lines and enh 2p22pter in HUR-resistant cells. Conclusions: Enh or amp 5q13q14 corresponds to the locus of dihydrofolate reductase which causes resistance to MTX. 7p21 is the locus of the multidrug resistance gene MDR1 involved in DOX-and VCR-resistance. Enh 2p22pter indicates the gain of ribonucleotide reductase M2 (RRM2) which confers resistance to HUR. Further investigations will clarify, whether other loci altered in resistant lines are causative for drug resistance or unspecifically altered during progresion or drug selection.

KEY WORDS: Chemotherapy, Drug resistance, Comparative genomic hybridization.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Multidrug Resistance - MDR.