Chemotherapeutic deletion of CTG repeats in lymphoblast cells from DM1 patients.
Myotonic dystrophy type 1 (DM1) is caused by the expansion of a (CTG).(CAG) repeat in the DMPK gene on chromosome 19q13.3. At least 17 neurological diseases have similar genetic mutations, the expansion of DNA repeats. In most of these disorders, the disease severity is related to the length of the repeat expansion, and in DM1 the expanded repeat undergoes further elongation in somatic and germline tissues. At present, in this class of diseases, no therapeutic approach exists to prevent or slow the repeat expansion and thereby reduce disease severity or delay disease onset. We present initial results testing the hypothesis that repeat deletion may be mediated by various chemotherapeutic agents. Three lymphoblast cell lines derived from two DM1 patients treated with either ethylmethanesulfonate (EMS), mitomycin C, mitoxantrone or doxorubicin, at therapeutic concentrations, accumulated deletions following treatment. Treatment with EMS frequently prevented the repeat expansion observed during growth in culture. A significant reduction of CTG repeat length by 100-350 (CTG).(CAG) repeats often occurred in the cell population following treatment with these drugs. Potential mechanisms of drug-induced deletion are presented.
Hashem
Vera I
VI
Center for Genome Research, Institute of Biosciences and Technology, Texas A&M University System Health Sciences Center, 2121 West Holcombe Boulevard, Houston, TX 77030-3303, USA.
Pytlos
Malgorzata J
MJ
Klysik
Elzbieta A
EA
Tsuji
Kuniko
K
Khajavi
Mehrdad
M
Khajav
Merhdad
M
Ashizawa
Tetsuo
T
Sinden
Richard R
RR
D000483:Alleles; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D002460:Cell Line; D004317:Doxorubicin / Q000627:therapeutic use; D005020:Ethyl Methanesulfonate / Q000627:therapeutic use; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D016685:Mitomycin / Q000627:therapeutic use; D008942:Mitoxantrone / Q000627:therapeutic use; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects*
D018906:Antineoplastic Agents, Alkylating; D016685:Mitomycin; D004317:Doxorubicin; D005020:Ethyl Methanesulfonate; D008942:Mitoxantrone