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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1755. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lin, T. S. Search for Related Content PubMed Articles by Lin, T. S. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Roos et al, page 2246 Do short telomeres shorten CLL survival? Thomas S. Lin THE OHIO STATE UNIVERSITY Roos and colleagues demonstrate that telomere length correlates with known biological prognostic factors in CLL and may independently predict clinical outcome. These findings suggest that telomerase may be a useful pharmacological target in CLL. Patients with chronic lymphocytic leukemia (CLL) exhibit greatly variable clinical behavior; some patients do not require therapy for years or decades, whereas others progress rapidly, respond poorly to therapy, and die within a few years. Over the past decade, significant advances in our understanding of the prognostic importance of cytogenetic abnormalities and other biological factors in the natural history of CLL have greatly improved clinicians' ability to identify patients who are likely to do poorly and may require more aggressive treatment. This risk stratification provides essential information on the percentage of high-risk patients in a clinical protocol, and is critical for interpretation of clinical trial results. Furthermore, risk stratification allows researchers to target high-risk populations in clinical studies of new regimens and agents in CLL. Deletion of 17p13 and 11q22, corresponding to loss of the p53 and ataxia telengiectasia mutated (ATM) tumor suppressor genes, respectively, is associated with a need for earlier therapy and poor long-term prognosis. Similarly, patients with an unmutated immunoglobulin heavy chain variable region (IgVH) have a markedly inferior prognosis compared with patients who have unmutated IgVH. However, IgVH mutational analysis is expensive and, until recently, reliable IgVH mutational assessment was not available outside specialized academic centers. Therefore, investigators have examined prognostic factors such as CD38 and zeta-associated protein (ZAP)–70, whose expression correlates with unmutated IgVH and inferior long-term survival. In this issue of Blood, Roos and colleagues report an inverse correlation between telomere length and unmutated IgVH status, ZAP-70 expression, and CD38 expression in a cohort of 152 patients with CLL. Furthermore, a solitary del(13q) cytogenetic abnormality, which is associated with a favorable prognosis, was observed more frequently in patients with a telomere length above the median than in patients with short telomeres. In contrast, deletions of 11q or 17p, which confer an inferior prognosis, were more common in patients with short telomeres. More importantly, the authors demonstrate that telomere length correlates with clinical outcome. Patients with telomere lengths below the median had poorer long-term treatment-free and overall survival compared with patients with long telomeres. In fact, multivariate analysis using clinical stage, IgVH mutational status, ZAP-70, CD38, and telomere length as variables identified only clinical stage and telomere length as independent prognostic factors for treatment-free survival. These important findings indicate that telomere length may be a useful independent prognostic factor in the risk stratification of CLL patients, although further studies are needed to confirm these results. These findings suggest that the enzyme telomerase, which is overexpressed in CLL and other hematologic malignancies, may be a target for novel anticancer therapies, particularly in those patients whose tumor cells feature shortened telomeres. The phosphorothioate oligonucleotide GRN163L targets telomerase and is in phase 1 clinical study at The Ohio State University and other institutions. Similar studies are planned for other diseases, such as multiple myeloma and myelodysplasia, with increased telomerase activity. Roos and colleagues' identification of telomere length as a biological prognostic factor in CLL provides further rationale for these clinical studies. Hopefully, targeting telomerase will translate into effective clinical therapy for CLL patients. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Short telomeres in B-CLL: the chicken or the egg? Bernd Jahrsdörfer and George J. Weiner Blood 2008 111: 5756. [Full Text] [PDF] Response: Or both? Göran Roos, Richard Rosenquist, and Stephan Stilgenbauer Blood 2008 111: 5756-5757. [Full Text] [PDF] Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia Göran Roos, Alexander Kröber, Pawel Grabowski, Dirk Kienle, Andreas Bühler, Hartmut Döhner, Richard Rosenquist, and Stephan Stilgenbauer Blood 2008 111: 2246-2252. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lin, T. S. Search for Related Content PubMed Articles by Lin, T. S. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?

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