Biological Risk Prediction in Chronic Lymphocytic Leukemia with Emphasis on CLLU1 Expression

Objectives: Chronic lymphocytic leukemia (CLL) is anincurable disease with a highly variable clinical course. IgVH mutationalstatus, chromosomal aberrations, CD38 expression and ZAP-70expression are prognostic markers in CLL, however, they are notexclusively confined to this disease. We recently identified a novel CLL-specific gene (CLL upregulated gene1, CLLU1) that is exclusively up-regulated in CLL cells. Here we describe our evaluation of the prog-nostic significance of CLLU1 in CLL. Methods: A cohort of 59previously untreated CLL patients was studied. We determined theexpression levels of two CLLU1 transcripts, cDNA1 and CDS, by quan-titative RT-PCR. The relation between CLLU1 expression and time totherapy, overall survival and presence or absence of ZAP-70, CD38,chromosomal aberrations or IgVH mutations in the 59 patients was ana-lyzed. Results: Analyzed as a continuous, quantitative parameterCLLU1 levels significantly predicted time from diagnosis to initiationof therapy (P £ 0.0003) Analyzed as a categorical parameter, bysegregation of the patients into groups with cDNA1 or CDSexpression above or below the median, the CLLU1 levels significantlypredicted time from diagnosis to initiation of therapy (P 1⁄4 0.001) andpredicted overall survival with borderline significance (P £ 0.05).Patient stratification according to clinical stage, cytogenetics, IgVHmutational status, ZAP-70 and CD38, demonstrated significantlyincreased CLLU1 expression in all investigated CLL poor riskgroups. CLLU1 expression levels contributed additional prognosticinformation to ZAP-70-positive patients. Conclusions: CLLU1 isthe first identified CLL specific gene. The CLLU1 mRNA expressionlevel can predict time to initiation of treatment and survival inCLL patients.Anne Mette Buhl, JesperJurlander, Christian HartmannGeisler, Lone Bredo Pedersen,Mette Klarskov Andersen,PärJosefsson, Jørgen HolmPetersen, Henrik LeffersDepartment of Hematology, The Leukemia Laboratory,Rigshospitalet, Denmark; Department of ClinicalGenetics, Rigshospitalet, Denmark;The UniversityDepartment of Growth and Reproduction,Rigshospitalet, Denmark; Department of Biostatistics,University of Copenhagen, Denmark