CLLU1 expression levels predict time to initiation of therapy and overall survival in chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the Western world with an annual incidence of 5/100 000 (1). Unlike many other hematological malignancies, the pathogenesis of CLL has not been related to deregulated expression of a disease-specific gene and CLL remains incurable with conventional therapy. Chronic lymphocytic leukemia results from the accumulation of slowly proliferating, long lived, CD5-positive B-cells with apoptotic defects (2). The clinical course of the disease is highly variable; while some patients with CLL experience a stable clinical course that will never affect their morbidity or mortality, the majority of CLL patients will eventually progress to a truly malignant disease and experience repeated courses of chemotherapy with decreasing effectiveness. The steadily increasing tumor burden is accompanied by progressive bone marrow failure, lymph node enlargement and immune deficiency, leading to wasting, infections, Buhl AM, Jurlander J, Geisler CH, Pedersen LB, Andersen MK, Josefsson P, Petersen JH, Leffers H. CLLU1 expression levels predict time to initiation of therapy and overall survival in chronic lymphocytic leukemia. Abstract: Objectives: Chronic lymphocytic leukemia (CLL) is an incurable disease with a highly variable clinical course. IgV H mutational status, chromosomal aberrations, CD38 expression and ZAP-70 expression are prognostic markers in CLL, however, they are not exclusively 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 59 previously untreated CLL patients was studied. We determined the expression levels of two CLLU1 transcripts, cDNA1 and CDS, by quan- titative RT-PCR. The relation between CLLU1 expression and time to therapy, overall survival and presence or absence of ZAP-70, CD38, chromosomal aberrations or IgV H mutations in the 59 patients was ana- lyzed. Results: Analyzed as a continuous, quantitative parameter CLLU1 levels significantly predicted time from diagnosis to initiation of therapy (P £ 0.0003) Analyzed as a categorical parameter, by segregation of the patients into groups with cDNA1 or CDS expression above or below the median, the CLLU1 levels significantly predicted time from diagnosis to initiation of therapy (P ¼ 0.001) and predicted overall survival with borderline significance (P £ 0.05). Patient stratification according to clinical stage, cytogenetics, IgV H mutational status, ZAP-70 and CD38, demonstrated significantly increased CLLU1 expression in all investigated CLL poor risk groups. CLLU1 expression levels contributed additional prognostic information to ZAP-70-positive patients. Conclusions: CLLU1 is the first identified CLL specific gene. The CLLU1 mRNA expression level can predict time to initiation of treatment and survival in CLL patients. Anne Mette Buhl 1 , Jesper Jurlander 1 , Christian Hartmann Geisler 1 , Lone Bredo Pedersen 1 , Mette Klarskov Andersen 2 , Pär Josefsson 1 , Jørgen Holm Petersen 3,4 , Henrik Leffers 3 1 Department of Hematology, The Leukemia Laboratory, Rigshospitalet, Denmark; 2 Department of Clinical Genetics, Rigshospitalet, Denmark; 3 The University Department of Growth and Reproduction, Rigshospitalet, Denmark; 4 Department of Biostatistics, University of Copenhagen, Denmark Key words: chronic lymphocytic leukemia; chronic lymphocytic leukemia upregulated gene1; prognostic factor; outcome Correspondence: Anne Mette Buhl, Department of Hematology, 4041, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark Tel: +45-35-454045 Fax: +45-35-454295 e-mail: am.buhl@get2net.dk Accepted for publication 30 December 2005 Eur J Haematol 2006: 76: 455–464 doi:10.1111/j.0902-4441.2005.t01-1-EJH2530.x All rights reserved Eur J Haematol 2006: 76: 455–464 doi:10.1111/j.0902-4441.2005.t01-1-EJH2530.x All rights reserved Ó 2006 The Authors Journal compilation Ó 2006 Blackwell Munksgaard EUROPEAN JOURNAL OF HAEMATOLOGY 455