Arsenic inhibition of telomerase transcription leads to genetic instability

Arsenic is effective in the treatment of acute promyelocytic leukemia. Para doxically, it is also carcinogenic. In the process of elucidating a mechani sm of arsenic resistance in a leukemia cell line, NB4, we discovered that a rsenic exposure causes chromosomal abnormalities, with a preponderance of e nd-to-end fusions. These chromosomal end fusions suggested that telomerase activity may be inhibited by arsenic. We found that arsenic inhibits transc ription of the hTERT gene, which encodes the reverse transcriptase subunit of human telomerase. This effect may in part be explained by decreased c-My c and Spl transcription factor activities. Decreased telomerase activity le ads to chromosomal end lesions, which promote either genomic instability an d carcinogenesis or cancer cell death. These phenomena may explain the seem ingly paradoxical carcinogenic and antitumor effects of arsenic.