Subsequential Alterations of Telomeric DNA Length Correlate with Cytogenetic Response in Chronic Myeloid Leukemia Treated with Interferon alpha

Abstract

Telomeres consist of simple tandem hexametric (TTAGGG) repeats and progressively shorten with cell replication. To determine a relationship between telomeric erosion and response to treatment, we measured telomere length following treatment in patients with chronic myeloid leukemia (CML) in the chronic phase. We used 70 samples of bone marrow mononuclear cells obtained from 26 patients with CML in the chronic phase subsequently. Telomere length was determined by a Southern hybridization of HinfI-digested DNA using a (TTAGGG)₄ probe, and the terminal restriction fragment (TRF) length was measured. Telomerase activity was also measured in 14 CML patients at the time of diagnosis using a telomeric repeat amplification protocol (TRAP) assay. Of the 26 patients with CML at the time of diagnosis, 14 had normal TRF lengths and the remaining 12 had shortened TRFs compared to those of age-matched normal individuals. In a group of CML patients treated with interferon alpha (IFNα), 80% of those who showed normal TRFs obtained cytogenetic responses. Approximately 50% of patients with shortened TRFs and treated with IFNα showed normalization of TRFs after IFNα treatment and all of them were cytogenetic responders. None of the CML patients with shortened TRFs before and after IFNα treatment achieved major cytogenetic response and they had high levels of telomerase activity. In the group of CML patients treated with hydroxyurea alone, although some patients showed normalization of TRF lengths after treatment, none of them showed major cytogenetic response. Telomere length before treatment may be related to CML disease severity. Cytogenetic response could be expected in CML patients with normal TRF lengths and treated with IFNα. Thus, measurement of telomere length after treatment might provide important information in managing CML patients.

Keywords:

• Chronic myeloid leukemia
• telomere length
• cytogenetic response
• interferon alpha