CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4973-4979 ◽  
Author(s):  
Pär Josefsson ◽  
Christian H. Geisler ◽  
Henrik Leffers ◽  
Jørgen H. Petersen ◽  
Mette K. Andersen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Risk Prediction ◽  
Expression Analysis ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Specific Gene ◽  
Prognostic Information ◽  
Expression Levels ◽  
Mutational Status ◽  
Igvh Mutational Status

AbstractWe recently identified a disease-specific gene CLLU1 in chronic lymphocytic leukemia (CLL) and also demonstrated that high CLLU1 expression levels predict poor clinical outcome. To validate this finding, we measured CLLU1 mRNA expression levels by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) in 175 patients with CLL. Analyses of IgVH mutational status, ZAP-70 expression, CD38 expression, and chromosomal aberrations were also performed. High levels of CLLU1 expression were associated with shorter overall survival (P < .001), with a 7% increase in risk of early death by each doubling of the CLLU1 expression level. Stratification for age at diagnosis demonstrated a strong prognostic significance of CLLU1 expression in patients younger than 70 years (P < .001), but not in patients aged 70 or older (P = .61). The prognostic significance of IgVH mutational status and ZAP-70 expression had a similar age-dependent variation. Multivariate analysis in the younger age group showed that CLLU1 expression analysis added further prognostic information within all prognostic subgroups, with the exception of patients with unmutated IgVH CLL. Only CLLU1 expression and IgVH mutational status had independent predictive power. Thus, analysis of CLLU1 expression is highly applicable in risk prediction in CLL for patients of an age eligible for risk stratification.

scholarly journals EXPRESSION OF LIPOPROTEIN LIPASE AND c-MYC ONCOGENE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AFFECTED BY THE CHORNOBYL ACCIDENT

2020 ◽  
Vol 25 ◽  
pp. 421-429
Author(s):  
N. Bilous ◽  
◽  
I. Abramenko ◽  
A. Chumak ◽  
I. Diagil ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lipoprotein Lipase ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
Expression Levels ◽  
Myc Oncogene ◽  
Mutational Status ◽  
Ighv Gene ◽  
Lpl Gene ◽  
Myc Gene

Objective. to determine the association between the expression of lipoprotein lipase (LPL) and c-MYC genes in peripheral blood cells of chronic lymphocytic leukemia (CLL) patients affected by the Chornobyl catastrophe depending on the mutational status of IGHV genes. Methods. Analysis was performed in the group of 69 CLL patients irradiated due to the Chornobyl NPP accident (58 clean-up workers of 1986 year, 6 inhabitants of radionuclide contaminated areas, and 5 evacuees). The IGHV gene mutational status was studied by polymerase chain reaction (PCR) followed by direct sequencing. LPL and c-MYC expression was evaluated by Quantitative Real-time PCR. Data were analyzed with the SPSS software package, version 20.0. Results. Relative LPL expression levels in CLL samples ranged from 0 to 1663.5 (mean 138.47 ± 30.69, median 26.1). A strong correlation between individual LPL expression levels and IGHV mutational status was found (r = 0.684; p < 0.0001). The average relative c-MYC expression level was 5.7 ± 0.87 (median 2.86; range 0–48.5). No association between c-MYC expression and IGHV mutational status was found. Among unmutated IGHV cases, a correlation between LPL and c-MYC gene expression levels was identified: r = 0.351; p = 0.013. Conclusions. Our data confirm the dominant concept that unmutated IGHV CLL cases are more sensitive to the action of proliferative stimuli compared to mutated IGHV CLL cases. This is manifested by an increase in the expression of a functionally significant LPL gene, is one for the strongest negative prognostic markers in CLL. Key words: lymphocytic leukemia, LPL, c-MYC, IGHV genes, Chornobyl NPP accident.

Dexamethasone Induces Apoptosis “Ex Vivo” in Chronic Lymphocytic Leukemia Cells with Either Unmutated IgVH Genes or High ZAP-70 Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2945-2945
Author(s):  
Ana Muntanola ◽  
Marta Crespo ◽  
Eva Gine ◽  
Neus Villamor ◽  
Emili Montserrat ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Viability ◽  
Ex Vivo ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Prognostic Features ◽  
Mutational Status ◽  
Cell Mortality ◽  
Igvh Mutational Status ◽  
Induced Apoptosis

Abstract Patients with chronic lymphocytic leukemia (CLL) and unmutated IgVH genes or high ZAP-70 expression have poorer prognosis than those with mutated IgVH genes or low ZAP-70 levels. This is in part related to the resistance of unmutated and ZAP-70 positive cases to treatment agents that induce apoptosis in a p53-dependent manner. It has been suggested that corticosteroids are active in CLL through p53-independent pathways. The aim of this study was to analyze the “ex vivo” response to dexamethasone in CLL cells according to the IgVH mutational status and ZAP-70 expression. Frozen lymphocytes from 60 patients with CLL were analyzed for ZAP-70 expression and IgVH mutational status (n=44). Cells were cultured and treated using fludarabine (5μgr/ml), mitoxantrone (0.5μgr/ml), FCM (fludarabine 1μgr/ml, maphosphamide 1μgr/ml and mitoxantrone 0.5 μgr/ml), and dexamethasone (5.2 μg/mL). Cell viability and apoptosis were determined by annexinV/PI staining and FACscan analysis at three different time points and conditions (0h and 24h without treatment, and 24h with treatment). The expression of glucocorticoid receptor (GR) isoforms alpha, beta and gamma was analyzed by Quantitative RT-PCR in 20 cases. Dexamethasone-induced apoptosis was significantly higher in patients with unmutated IgVH and/or high ZAP-70 expression (≥20%) than in those with mutated IgVH and/or low ZAP-70 expression (median cell viability 65% vs. 81%, respectively; p&lt;0.001). In contrast, mitoxantrone induced higher cell toxicity in patients with IgVH mutations or low ZAP-70 expression (p=0.009). No differences in cell viability were found according to ZAP-70 expression or IgVH mutational status after “ex vivo” treatment with fludarabine or FCM (p=0.649 and p=0.055, respectively). Expression of different GR isoforms was similar in corticosteroid-responders and non-responders. In conclusion, in this study CLL cells with unmutated IgVH genes or high ZAP-70 expression showed a higher cell mortality after “ex vivo” exposure to dexamethasone than those with mutated IgVH genes or low ZAP-70 expression, with no relationship with the expression of the different GR isoforms. These data give conceptual support to trials aimed at determining the role of dexamethasone in the treatment of patients with CLL and poor prognostic features or resistant to fludarabine. Figure Figure

MicroRNA-29c and 223 Are Powerful Prognostic Factors for Chronic Lymphocytic Leukemia and Improve Risk Stratification When Combined with ZAP70 and LPL in a qPCR Score.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1066-1066
Author(s):  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Dominique Bron ◽  
Benjamin Haibe-Kains ◽  
Pascale Saussoy ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Lymphocytic Leukemia ◽  
Early Therapy ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Binet Stage

Abstract Background: MicroRNAs (or miR) are a novel class of small noncoding RNA involved in gene regulation. Aberrant microRNA expression has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Currently, the heterogeneous evolution of this disease can be predicted by several prognostic factors. Nevertheless, a better individualization of the outcome in a given patient is still of utmost interest. Methods: In the current study, we investigated the expression of two microRNAs, miR-29c and miR-223, compared them to other biological or clinical markers and proposed a quantitative real-time PCR (qPCR) score to better assess CLL outcome. All cut-offs were calculated by ROC curve analysis maximising the correlation with the immunoglobulin variable heavy chain (IgVH) mutational status; statistical differences were evaluated by Mann Whitney test or Kruskal-Wallis test ; treatment-free (TFS) and overall (OS) survival differences were investigated by log-rank test or Cox proportional hazard ratio (HR). Results: miR-29c and miR-223 expression decreased significantly with progression along Binet Stage A to C (P=0.0010 and P=0.0183, respectively), and were significantly lower in poor prognosis subgroups defined by cytogenetic abnormalities, IgVH mutational status, lymphocyte doubling time, solubleCD23, β2-microglobulin, ζ-associated protein 70 (ZAP70), lipoprotein lipase (LPL) and CD38 expression. Furthermore, miR-29c and miR-223 could predict TFS (n=110, P=0.0015 and P&lt;0.0001, respectively) and OS (n=110, P=0.0234 and P=0.0008, respectively). Regarding all these results, we developed a qPCR score (from 0 to 4 poor prognostic markers) combining miR-29c, miR-223, ZAP70 and LPL in order to stratify treatment and death risk in a 110 patient cohort with a median follow-up of 72 months (range, 2–312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of &gt;312, 129, 80, 36 and 19 months, respectively (HR=17.00, P&lt;0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of &gt;312, 183 and 106 months, respectively (HR=13.69, P=0.0001). Interestingly, during the first 50 months after diagnosis, only 10% of patients with a 0/4 score required a treatment, when compared to 100% of the 4/4. Furthermore, during the total follow-up (312 months), patients with a 4/4 score had a 27-fold higher risk to be treated and a 31-fold higher risk to die comparing to patients with a 0/4 score. This score was validated by a 10-fold cross-validation (prediction accuracy of 82%). Finally, in Binet stage A patients (n=77), this score remained relevant and significant for TFS and OS prediction (HR=18.56, P&lt;0.0001 and HR=12.5, P=0.0068, respectively). Conclusions: we showed that (i) miR-29c and miR-223 levels were decreased in poor prognosis patients regarding several well-known prognostic factors; (ii) a low level of these two microRNAs is thus associated to disease aggressiveness, tumor burden and poor clinical evolution; (iii) we also showed that these two microRNAs could predict TFS and OS; (iv) we proposed a qPCR score to better individualize evolution of a particular CLL patient. This score will help to identify patients who will need early therapy and require thus a closer follow-up.

Clinical-Biological Characterization of Variant B Chronic Lymphocytic Leukemia, Characterized by a Mantle Cell Lymphoma-Like Immunophenotype, t(11;14)(q13;q32) Negative.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1259-1259
Author(s):  
Andrea Ferrario ◽  
Lilla Cro ◽  
Nadia Zucal ◽  
Marta Lionetti ◽  
Francesco Bertoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Statistical Difference ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Mutational Status ◽  
Mantle Cell ◽  
Igvh Mutational Status

Abstract Abstract 1259 Poster Board I-282 We describe the clinical-biological features of 63 cases of variant B chronic lymphocytic leukemia (v-B-CLL), characterized by a mantle cell lymphoma-like immunophenotype, atypical cytomorphology in absence of t(11;14)(q13;q32) in FISH analysis. A historical series of 130 B-CLL was used as comparison. The v-B-CLL were significantly different from the B-CLL in terms of the following clinico-hematological variables: age <70 yrs (p <.001), lymphocytosis <20 × 109/ (p <.001), lymphocyte doubling time < 12 months (p = .02), high serum β2-microglobulin levels (p <.001), and splenomegaly (p = .002). Considering immunophenotipic features, CD38 and CD49d expression were significantly more expressed in v-B-CLL than B-CLL (p <.001); whereas, no statistical difference was observed for ZAP-70 reactivity. Considering the IgVH mutation status, there were more patients mutated in the v-B-CLL group than in the B-CLL group (p = .001). Other significant differences were found about the frequency of the recurrent chromosome alterations, evaluated by means of FISH analysis: trisomy 12 was more frequent in v-B-CLL ( p<.001), while del13q14, considered as a single alteration, was more frequent in B-CLL (p=.008). Gene expression profiling of a panel of 9 v-B-CLL compared with 60 B-CLL samples indicated that the variant group is characterized by a specific molecular pattern of gene expression. In particular we observed the upregulation of tumor protein D52 (TPD52), and that of 6 genes (AFF1, GMPS, PICALM, JUN, REL, RAC2) known to be protooncogenes. Furthermore, we found that upregulated genes with apoptosis related functions (IL-7, HSP90B1, NOTCH2, BECN1, ANXA4, MCL1) are all negative regulators of apoptosis. Microarray analysis revealed that various genes (TRIM38, EEF1D, CASP1, MALT1, RHOH0) involved in the I-kB kinase/NF-kB cascade of the canonical NF-kB signaling pathway, are furtherly upregulated in v-B-CLL. Furthermore, among the genes found differentially expressed in SAM analysis, we observed also the upregulation of CD1c (according to the surface expression of this antigen), OSBPL3 and ITGA4. After a median follow-up of 55 months (range 4-196) and 60 months (range 6-180), 25/42 (59%) v-CLL and 55/93 (59 %) CLL pts were treated. TTT was significant different between 2 groups when the IgVH mutational status was considered (p= .006). Median OS of v-CLL subset was 112 months vs 171 months of CLL subset. When the IgVH mutational status was considered, mutated cases showed a worse OS even if a statistical difference was not observed (p= 0.062). In conclusion, our study identifies, on the basis of a defined CFM-FISH diagnostic approach, a variant form of B-CLL that shows peculiar biological and clinical features that should be considered in the future clinical and prognostic studies. The inclusion of this form in B-CLL study could alter the interpretation of results, especially related to biological markers. Disclosures No relevant conflicts of interest to declare.

Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 853-861 ◽  
Author(s):  
Maria Ilaria Del Principe ◽  
Giovanni Del Poeta ◽  
Francesco Buccisano ◽  
Luca Maurillo ◽  
Adriano Venditti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Staging ◽  
Mutational Status ◽  
Staging Systems ◽  
Cell Chronic Lymphocytic Leukemia

Abstract The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zeta-associated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70+ (P < .001), in CD38+ (P < .001) and in sCD23+ patients (P < .001 and P = .013, respectively). ZAP-70+CD38+ or ZAP-70+ patients with an unmutated IgVH status showed both a shorter PFS (P < .001) and OS (P < .001 and P < .001, respectively) as compared with ZAP-70–/CD38– or ZAP-70– patients with mutated IgVH genes. Discordant patients showed an intermediate outcome. Note, ZAP-70+ patients even if CD38– or mutated showed a shorter PFS, whereas ZAP-70– patients even if CD38+ or unmutated had a longer PFS. Furthermore, ZAP-70 positivity was associated with a shorter PFS both within normal karyotype (P < .001) and within the poor-risk cytogenetic subset (P = .02). The predictive value of ZAP-70 expression was confirmed in multivariate analysis. Thus, ZAP-70 protein determined by flow cytometry improves the prognostic significance of cytogenetics and appears to be a better predictor of outcomes than IgVH gene mutational status. On this line, we recommend and are also interested in conducting a prospective randomized trial of early intervention versus observation for ZAP-70+ patients.

scholarly journals Proteins interaction network and modeling of IGVH mutational status in chronic lymphocytic leukemia

2015 ◽  
Vol 12 (1) ◽  
Author(s):  
María Camila Álvarez-Silva ◽  
Sally Yepes ◽  
Maria Mercedes Torres ◽  
Andrés Fernando González Barrios
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Interaction Network ◽  
Lymphocytic Leukemia ◽  
Mutational Status ◽  
Igvh Mutational Status

Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997

2007 ◽  
Vol 25 (7) ◽  
pp. 799-804 ◽  
Author(s):  
Michael R. Grever ◽  
David M. Lucas ◽  
Gordon W. Dewald ◽  
Donna S. Neuberg ◽  
John C. Reed ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Variable Region ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Therapeutic Trial ◽  
Cd38 Expression ◽  
Molecular Features ◽  
Mutational Status

Purpose Genomic features including unmutated immunoglobulin variable region heavy chain (IgVH) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome. Patients and Methods We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients. Results Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgVH mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS. Conclusion These results support the use of interphase cytogenetic analysis, but not IgVH, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.

Predictive Value of Gene Expression with Respect to IgVH Mutational Status and Survival in Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1913-1913
Author(s):  
Mars B. Van’t Veer ◽  
Anne Brooymans ◽  
Anton W. Langerak ◽  
Wilfried J. Graveland ◽  
Kirsten Van Lom ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Predictive Value ◽  
Cox Regression ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Mrna Levels ◽  
Cox Regression Analysis ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Prediction Of Prognosis

Abstract Background: Chronic Lymphocytic Leukemia (CLL) has a variable clinical course, of which IgVH mutational status of the malignant B cells is a strong independent predictor for outcome. Objective: We studied the expression of 5 different genes for their value to predict IgVH mutational status and overall survival (OS). Methods: mRNA levels were quantified by real time PCR in lymphoprep separated but unsorted blood samples from 110 morphologically and fenotypically characterised CLL patients for the following genes: ZAP70, lipoprotein lipase (LPL), ADAM29, KIAA0610 and nRIP1. Expression levels were compared wih respect to IgVH mutational status (mutation = % germline < 98%), using logistic regression and with respect to OS (= time from day of laboratory tests to death due to any cause), using Cox regression analysis. Results: The predictive value of the expression of these 5 genes for IgVH mutational status is shown in table 1. Each of these genes showed to be an independent marker for the prediction of IgVH mutational status. LPL as a single marker was the best predictor for mutation. These factors taken together had a high predictive value towards mutational IgVH status (area under ROC curve = 0.93). table 1 N Odds ratio P value ZAP70 no 85 1 (>5.2) yes 25 0.098 0.002 LPL no 73 1 (>0.04) yes 37 0.029 <0.001 ADAM29 no 73 1 (>30) yes 37 6.61 0.012 KIAA0610 no 81 1 (>0.25) yes 29 0.19 0.045 NRIP1 no 88 1 (>10) yes 22 48.73 0.008 The predictive value of IgVH mutation and the expression of these 5 genes for OS is shown in table 2. From the six parameters tested, IgVH mutational status and LPL were predictors for OS at a significant level of 5%, while ZAP70 was of borderline significance. table 2 Conclusion: measured in unsorted CLL samples, all genes, and especially LPL, had predictive value towards the presence of IgVH mutation. Expression of LPL and absence of mutation were adverse prognostic factors for survival. Thus, the replacement of the assessment of both IgVH mutational status and ZAP70 by assessment of LPL levels for the prediction of prognosis in CLL patients may be considered. N survival at 24months P value mutation no 36 70% yes 44 93% 0.041 ZAP70 no 66 87% yes 18 70% 0.078 LPL no 55 94% yes 29 66% 0.001 ADAM29 no 57 84% yes 27 84% 0.486 KIAA0610 no 63 88% yes 21 71% 0.133 NRIP no 71 81% yes 13 100% 0.167

Validation of the Prognostic Significance of the Disease Specific Gene CLLU1 in Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 709-709 ◽  
Author(s):  
Par Josefsson ◽  
Jesper Jurlander ◽  
Christian H. Geisler ◽  
Lone B. Pedersen ◽  
Lone Bach ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Expression Level ◽  
Specific Gene ◽  
Cd38 Expression ◽  
Mutational Status ◽  
Time To Initiation ◽  
Significant Difference ◽  
Disease Specific

Abstract We have recently identified and cloned a novel disease specific gene CLLU1, with a strong prognostic significance in a small test cohort of CLL patients (ASH 2004, #770). To validate this finding in a larger series, 176 newly diagnosed, previously untreated CLL patients referred to Rigshospitalet, Copenhagen in 1991–1999, were investigated. Clinical characteristics of the population were: 116 stage A patients (66 %), median age 69.9 years, 98 males (56%), median follow up 59 months. The end points for the statistical analysis were overall survival and time to initiation of treatment. At time of analysis 91 (52%) patients had died and 104 (59%) had commenced treatment. Frozen patient samples, taken at time of diagnosis, were investigated for CLLU1 expression, as well as for mutational status, CD38 expression, ZAP-70 expression and cytogenetic aberrations. CLLU1 expression was assayed by QRT-PCR using the cDNA1 splice variant, and expressed as fold upregulation above the CLLU1 level in normal B-cells. CD38 and ZAP-70 analysis was performed by flow cytometry, using a 20 % cut-off level. Cytogenetic analysis was performed by FISH. The previously reported (ASH 2004, #770) median upregulation of CLLU1 in CLL cells was accurately reproduced and confirmed (25.5-fold (N = 176) vs. 27.7-fold (N = 59) in test population). Also in accordance with the pilot study, segregation of the patients based on the median CLLU1 expression level divided the population in two groups with significantly different times to initiation of treatment and borderline significant difference in overall survival. However, further analysis found an optimal cut-off level at 40-fold upregulation of CLLU1 expression; use of this cut-off demonstrated a highly significant difference in overall survival for patients with upregulated expression of CLLU1 (p = 0.0023). The median overall survival was 60.2 months for patients with CLLU1 expression above 40-fold compared to 100.8 months for the group with lower expression level. Likewise the time to initiation of first treatment was significantly shorter in the high-level expression group (p = 0.0018, median time to first treatment 9.3 months vs. 54.9 months). Furthermore, CLLU1 expression was upregulated in all poor prognostic subgroups investigated: Binet stage B or C, IgVH unmutated, unfavorable cytogenetics, high CD38 expression and high ZAP-70 expression. Our new study confirms that CLLU1 is a strong prognostic factor in CLL, comparable to other established prognostic markers. The exclusive upregulation of CLLU1 expression in CLL suggests a putative role for CLLU1 in the pathogenesis of CLL, and makes this gene a strong candidate for future gene-targeted treatment strategies. Figure Figure

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