Short Telomeres Are Associated with Genetic Instability and the Occurrence of High Risk Genomic Aberrations in Chronic Lymphocytic Leukemia.

Abstract Telomere length has been associated with the mutation status of the immunoglobulin variable heavy chain (VH) gene and the clinical course in chronic lymphocytic leukemia (CLL). In an unicentric CLL cohort of 108 patients, we have analyzed the telomere length by quantitative real time PCR, genomic aberrations by FISH with a comprehensive set of DNA probes (11q, 12q, 13q, 14q, 17p), the VH mutation status by DNA sequencing, ZAP-70 expression (clone 2F3.2, Upstate, according to Crespo et al., NEJM 2003) and CD38 expression by flow cytometry, to further study the prognostic impact and associations among these factors. A relative telomere-single-copy-gene ratio (T/S) was calculated for each sample, where low and high T/S values correspond to short and long telomere lengths, respectively. The median T/S value was 0.33 (range 0.06–1.18). There was an inverse correlation between telomere length and the following parameters: 1. VH homology (r=−0.56, p<0.001), 2. CD38 expression (r=−0.44, p<0.001) and 3. ZAP-70 expression (r=−0.25, p=0.01). Cases with T/S values below the median of 0.33 (short telomeres) and cases with T/S values above the median (long telomeres) had similar incidences of genomic aberrations (76 vs. 67%), 13q- (54 vs. 52%) and +12q (9 vs. 9%). In contrast, 13q- as a single aberration was significantly more frequently observed in cases with long telomeres (43 vs. 17%, p=0.006), whereas 11q- (30 vs. 9%, p=0.014), 17p- (24 vs. 0%, p<0.001) and cases with two or more genomic aberrations (26 vs. 6%, p<0.001) were significantly more frequent in cases with short telomeres. Compared to cases with long telomeres the treatment free survival from diagnosis (TFS) and overall survival (OS) in the group with short telomeres were significantly shorter (TFS: 29 vs. 67 months, p=0.002; OS: last observed death at 100 months, survival probability 57% vs. last observed death at 141 months, survival probability 77%, p=0.02). In conclusion, telomere length was inversely correlated with the VH mutation status, CD38 expression and ZAP-70 expression. Short telomeres were associated with genomic instability indicated by a high number of aberrations and the occurrence of 11q- and 17p- in CLL. These observations have biological and prognostic implications in CLL.

Download Full-text

Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2007-05-092759 ◽

2008 ◽

Vol 111 (4) ◽

pp. 2246-2252 ◽

Cited By ~ 90

Author(s):

Göran Roos ◽

Alexander Kröber ◽

Pawel Grabowski ◽

Dirk Kienle ◽

Andreas Bühler ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Telomere Length ◽

Inverse Correlation ◽

Prognostic Indicator ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Mutation Status ◽

Ighv Gene ◽

Genetic Complexity ◽

Genomic Aberrations

Telomere length is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). In a B-CLL cohort of 152 patients, we analyzed telomere length, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression to study the prognostic impact and associations among these factors. An inverse correlation existed between telomere length and IGHV homology (P < .001), CD38 (P < .001), and ZAP-70 expression (P = .01). Patients with telomere lengths below median (ie, “short telomeres”) and above median (ie, “long telomeres”) had similar incidences of genomic aberrations (74% vs 68%), 13q− (57% vs 49%), and +12q (5% vs 12%). In contrast, 13q− as a single aberration was more frequent in patients with long telomeres (51% vs 21%; P = .006), whereas 11q− (27% vs 9%; P = .014), 17p− (17% vs 0%; P < .001), and 2 or more genomic aberrations (39% vs 8%; P < .001) were more frequent in patients with short telomeres. Compared with patients with long telomeres, treatment-free survival (TFS) and overall survival (OS) was significantly shorter (P < .001 and P = .015, respectively) in the group with short telomeres, and telomere length was an independent prognostic indicator for TFS. These observations have biological and prognostic implications in B-CLL.

Download Full-text

V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v100.4.1410.h81602001410_1410_1416 ◽

2002 ◽

Vol 100 (4) ◽

pp. 1410-1416 ◽

Cited By ~ 558

Author(s):

Alexander Kröber ◽

Till Seiler ◽

Axel Benner ◽

Lars Bullinger ◽

Elsbeth Brückle ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Expression Level ◽

Chain Gene ◽

P Value ◽

Prognostic Impact ◽

Survival Times ◽

Mutation Status ◽

Cd38 Expression ◽

Genomic Aberrations

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed VH mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of VH mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (Pcor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% VH homology (95% confidence interval [CI], 96%-98% homology,Pcor <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, Pcor = .02). In univariate analyses, unmutated VH genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theVH unmutated and VHmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the VHunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theVH mutated subgroup. In multivariate analysis, unmutated VH, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of VH mutation status and genomic aberrations to predict outcome in CLL.

Download Full-text

Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.7184 ◽

2006 ◽

Vol 24 (6) ◽

pp. 969-975 ◽

Cited By ~ 134

Author(s):

Alexander Kröber ◽

Johannes Bloehdorn ◽

Sebastian Hafner ◽

Andreas Bühler ◽

Till Seiler ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Variable Region ◽

Multivariate Regression Analysis ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Mutation Status ◽

Characteristic Modes ◽

Genomic Aberrations ◽

Vh Gene

Purpose Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. Patients and Methods We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. Results ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. Conclusion There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

Download Full-text

Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status

Blood ◽

10.1182/blood-2004-11-4394 ◽

2005 ◽

Vol 105 (12) ◽

pp. 4807-4812 ◽

Cited By ~ 88

Author(s):

Pawel Grabowski ◽

Magnus Hultdin ◽

Karin Karlsson ◽

Gerard Tobin ◽

Anna Åleskog ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Telomere Length ◽

Gene Mutation ◽

Quantitative Polymerase Chain Reaction ◽

Lymphocytic Leukemia ◽

Prognostic Information ◽

Mutation Status ◽

Patient Groups ◽

Vh Gene ◽

Polymerase Chain

Abstract B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes. (Blood. 2005;105:4807-4812)

Download Full-text

Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v94.6.1840 ◽

1999 ◽

Vol 94 (6) ◽

pp. 1840-1847 ◽

Cited By ~ 1753

Author(s):

Rajendra N. Damle ◽

Tarun Wasil ◽

Franco Fais ◽

Fabio Ghiotto ◽

Angelo Valetto ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Gene Mutation ◽

Lymphocytic Leukemia ◽

Prognostic Indicators ◽

Risk Category ◽

Mutation Status ◽

Cd38 Expression ◽

Staging Systems ◽

V Genes ◽

V Gene

Abstract Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (<30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

Download Full-text

The TNF −308G>A Polymorphism Predicts Outcome of Patients with B-Cell Chronic Lymphocytic Leukemia In Relation to the IgVH Mutation Status

Blood ◽

10.1182/blood.v116.21.2421.2421 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2421-2421

Author(s):

Ewa Lech-Maranda ◽

Wojciech Mlynarski ◽

Olga Grzybowska-Izydorczyk ◽

Maciej Borowiec ◽

Krystyna Wyka ◽

...

Keyword(s):

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Newly Diagnosed ◽

First Line ◽

Mutation Status ◽

Free Survival ◽

Cd38 Expression ◽

Tnf Α ◽

Α Level ◽

First Line Treatment

Abstract Abstract 2421 Background: Tumor necrosis factor (TNF)–α is an important pro-inflammatory cytokine involved in the modulation of lymphoma development and the balance between cell-mediated and humoral immunity. Deregulated concentrations of TNF–α have been detected in patients with lymphoma and were associated with an adverse prognosis. Evidence that the single-nucleotide polymorphism (SNP) in TNF promoter, TNF −308G>A, could be the susceptibility locus for non-Hodgkin lymphoma (NHL) has been provided by case-control studies. Therefore we tested the hypothesis that TNF −308G>A influences clinical course of B-cell chronic lymphocytic leukemia (CLL). Patients and Methods: We genotyped TNF −308G>A (rs1800629) in 278 newly diagnosed patients with CLL and 192 ethnically-matched healthy individuals using the 7900 HT Real-Time (Applied Biosystems, USA). Some randomly selected DNA samples were analysed by direct sequencing using 3130xl Genetic Analyzer (Applied Biosystems, USA). Sequence data were based on the NCI SNP500 website. The IgVH mutation status in CLL patients was performed according to the protocol described by van Dongen et al. Serum samples from the 153 newly diagnosed CLL patients were collected at the time of diagnosis and tested by an enzyme-linked immunosorbent assay (ELISA) kit for human TNF (Quantikine, R&D Systems, USA). Results: The TNF −308G>A allelic frequencies and distributions were consistent with Hardy-Weinberg equilibrium, and did not differ significantly between CLL patients and the control group. There were no significant differences between TNF allelic or genotype distributions and clinical characteristics of CLL patients at diagnosis, including age, clinical stage according to Rai classification, serum LDH and β2-microglobulin levels, surface CD38 expression, ZAP-70 expression, Döhner's cytogenetic groups, and IgVH mutation status. Neither of assessed TNF polymorphic variants was associated with response to first-line treatment, progression free survival (PFS) nor treatment free survival (TFS) that was measured from time point of diagnosis to first therapy. With a median follow-up of surviving patients of 52 months (range 1–209 months), the group of patients with TNF (−308A) allele (TNF−308AA or TNF−308AG genotypes) had significantly shorter overall survival (OS) compared to those carrying TNF (−308GG) genotype (p=0.01, log–rank test). To further characterize the prognostic impact of genetic variation in TNF on CLL patients survival, we divided the patients according to the IgVH mutation status into a IgVH unmutated (homology ≥98%) and a IgVH mutated (homology <98%) group. We found that the patients carrying TNF (−308A) allele presented significantly shorter OS in the IgVH unmutated group compared to those with TNF (−308GG) genotype (p=0.02). Of note, the TNF −308G>A polymorphism did not influence survival of patients with the IgVH mutated gene. To further investigate this difference, we analyzed the impact of TNF SNP on serum TNF-α levels in CLL patients at the time of diagnosis. We found that high TNF-α levels, greater than the median (16.84 pg/mL) value, correlated with stages III and IV according to Rai classification (p=0.001, chi2 test), elevated serum levels of LDH (p=0.01) or β2-microglobulin (p=0.001), CD38 expression ≥30% (p=0.001), ZAP-70 expression >20% (p=0.01) as well as with TNF (−308AA) genotypes (p=0.04). The patients with high TNF-α levels had significantly shorter TFS (p<0.0001) compared to those with low cytokine levels. This association retained its prognostic impact on TFS both in the IgVH unmutated (p=0.004) and mutated (p<0.0001) group. No correlations between serum TNF-α levels and response to first-line treatment or PFS were found. Furthermore, in the group with high TNF-α levels, OS was significantly shorter compared to those in the cytokine low level group (p=0.04). Interestingly, when the patients were stratified according the IgVH mutation status, the high serum TNF-α level retained its prognostic impact on shorter OS only in the IgVH unmutated group compared to the patients with low TNF-α levels (p=0.04). Conclusions: Our results indicate that the TNF −308G>A polymorphism along with the serum TNF-α level may influence CLL outcome especially in the IgVH unmutated subgroup, which points out the importance of innate immunity genes for CLL variability and prognosis. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Telomere length and heavy-chain mutation status in familial chronic lymphocytic leukemia

Leukemia Research ◽

10.1016/s0145-2126(02)00010-3 ◽

2002 ◽

Vol 26 (9) ◽

pp. 791-794 ◽

Cited By ~ 16

Author(s):

Naoko Ishibe ◽

DaRue Prieto ◽

Douglas A Hosack ◽

Richard A Lempicki ◽

Lynn R Goldin ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Telomere Length ◽

Heavy Chain ◽

Lymphocytic Leukemia ◽

Mutation Status

Download Full-text

ZAP-70 Expression, VH-Mutation Status, Genomic Aberrations and Prognosis in Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.1920.1920 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1920-1920 ◽

Cited By ~ 1

Author(s):

Alexander Kröber ◽

Dirk Kienle ◽

Dirk Winkler ◽

Andreas Bühler ◽

Till Seiler ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Gene Rearrangement ◽

Progressive Disease ◽

Clinical Course ◽

Surrogate Marker ◽

Lymphocytic Leukemia ◽

Mutation Status ◽

Free Survival ◽

Genomic Aberrations

Abstract The VH status is a strong prognostic marker in chronic lymphocytic leukemia (CLL). ZAP-70, a zeta associated tyrosine kinase physiologically expressed by T-cells, is overexpressed in VH unmutated CLL and could therefore serve as a surrogate marker for the VH status. We analyzed ZAP-70 expression (n=96), the VH status (n=75) and genomic aberrations (n=84) in a single center CLL cohort to study associations among these parameters and to assess their relative prognostic value. ZAP-70 expression was measured by 4-colour flow cytometry (CD5, CD19, CD3/56, ZAP-70) applying an unconjugated anti-ZAP-70-antibody (Upstate, clone 2F3.2) according to Crespo et al., NEJM 2003. ZAP-70 expression was positive (cut-off 20%) in 67% and negative in 33% of cases. VH was mutated in 33% and unmutated in 67% of cases. Unfavorable genomic aberrations (17p−, 11q−) were more frequently observed in cases with unmutated VH (46 vs. 9%) and in ZAP-70 positive cases (39 vs. 20%), while favorable genomic aberrations (13q− as single aberration) occurred more frequently in VH mutated (48 vs. 17%) and ZAP-70 negative subgroups (50 vs. 18%). ZAP-70 expression predicted the VH status in 84% of cases. At a median follow up time of 47 months (m), the median treatment free survival (TFS) of ZAP-70 positive and negative cases was 31 and 86 m (p=.057). The median TFS of the VH unmutated and VH mutated subgroups were 24 and 172 m (p<.001). Within the follow up time 10 deaths occurred. Of these, 8 cases exhibited high ZAP-70 expression and an unmutated VH, whereas 2 cases showed discordant results. Overall, discordant results for ZAP-70 expression and VH status were identified in 12 cases (ZAP-70 positive/VH mutated, 8 cases; ZAP-70 negative/VH unmutated, 4 cases). Of the 8 VH mutated cases with high ZAP-70 expression, only 1 case exhibited unfavorable genomic aberrations, 4 remained in stable disease, 4 developed progressive disease, 3 patients required therapy, and 1 of these 3 died within follow up time. Two of the 3 patients who required therapy, including the patient who died, showed a mutated V3-21 gene rearrangement, associated with an unfavorable outcome. Among the 4 cases with an unmutated VH and low ZAP-70 expression, 2 cases exhibited unfavorable genomic aberrations, 3 cases required therapy, 1 of these 3 died, and for one patient no clinical data were available. In summary, the imbalanced distribution of high risk genomic aberrations was similar when comparing the subgroups according to ZAP-70 expression and VH status. In our series an unmutated VH status predicted for shorter TFS, whereas high ZAP-70 expression did not reach significance. ZAP-70 expression was associated with unmutated VH, but a substantial number of cases showed discordant results for ZAP-70 expression and VH status. The pattern of genomic aberrations and the clinical course of the discordant cases were typical for their respective VH status. Compared to ZAP-70 expression the VH status appeared to be more informative in the prediction of the clinical course in our series of CLL patients.

Download Full-text

Remarkable Differences in Cellular Activation State and Migratory and Proliferative Potential among Clonal Cells Derived from Different Tissues of Chronic Lymphocytic Leukemia Patients.

Blood ◽

10.1182/blood.v108.11.2817.2817 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2817-2817

Author(s):

Rajendra N. Damle ◽

Taraneh Banapour ◽

Sonal Temburni ◽

Tarun Wasil ◽

Jonathan E. Kolitz ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Telomere Length ◽

Telomerase Activity ◽

Lymphocytic Leukemia ◽

Proliferative Potential ◽

Activation Markers ◽

Cellular Activation ◽

Cd38 Expression

Abstract An antigen-independent process that takes place in the bone marrow (BM) leads to the birth of B cells from bone marrow precursors. Cross-talk between components of the microenvironment of BM or secondary lymphoid compartment(s), eg. spleen (SP), nurtures the subsequent evolution of B cells and governs in large part the natural history of normal B cells and B cell malignancies including chronic lymphocytic leukemia (B-CLL). Interaction of B cells with stromal elements confers upon them features enabling their transient sequestration, proliferation and extended survival. In this report we have compared the characteristics of clonal B-CLL cells obtained from paired specimens (peripheral blood, PB with corresponding BM or SP obtained within an interval of less than 1 month of each other) from 17 individual untreated B-CLL patients. These cells were tested by surface immunofluorescence and flow cytometry for their expression of a panel of chemokine receptors (CCR −1, −2, −4, and −7 and CXCR−1, −2, −3, and −4) and markers of cellular activation (CD23, CD62L, CD69, CD71 and HLA-DR). The relative age of the B cells (telomere length) and their ability to maintain telomere length (telomerase activity) were studied in paired BM/SP and PB samples from 15 of these cases. Although PB-, BM- and SP-derived B cells expressed activation markers, specifically, the percentages of cells expressing ZAP-70 and Ki-67 were significantly higher in BM- and SP-derived B cells than those expressed by corresponding PB-derived B cells (p<0.01). Increase in extent of CD38-positivity among members of the clone correlates with poor prognosis in B-CLL. Interestingly, in cases with low CD38 expression (<30% cells expressing CD38), the percentage of B-CLL cells expressing CXCR3 and CCR7 was significantly higher among PB-B cells, than BM/SP-derived B cells. No such differences existed in cases with high CD38 expression. This suggests a role for these receptors and their ligands in maintaining homeostasis of B-CLL cells in this subset of cases (that does not show remarkable progression of disease). In each of the 15 cases studied BM and SP-B cells had significantly higher telomerase activity (p<0.01) than those in PB, although telomere lengths of B cells from both sources were comparable. These findings highlight important differences in cellular kinetics among lymphoid compartments in B-CLL.

Download Full-text

LPL Is the Strongest Prognostic Factor in a Comparative Study of RNA-Based Markers in Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.1254.1254 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1254-1254

Author(s):

Mohd Arifin Kaderi ◽

Meena Kanduri ◽

Mahmoud Mansouri ◽

Anne Mette Buhl ◽

Marie Sevov ◽

...

Keyword(s):

Prognostic Factor ◽

Chronic Lymphocytic Leukemia ◽

Clinical Outcome ◽

Conflicts Of Interest ◽

Lymphocytic Leukemia ◽

Rna Expression ◽

Mutation Status ◽

Expression Levels ◽

Genomic Aberrations ◽

Binet Stage

Abstract Abstract 1254 Poster Board I-276 Introduction Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with varying clinical outcome, where many patients have an indolent course for many years, whereas others show a more aggressive disease despite treatment. This has prompted the search for biomarkers that can predict outcome in this disease. Recent studies have proposed the RNA expression levels of certain genes, i.e. LPL, CLLU1, TCL1, MCL1 and ZAP70 to be novel predictors of clinical outcome in CLL. However, a comprehensive assessment of these RNA-based markers is still lacking. The current study aimed to investigate the potential of these markers in CLL prognostication, either as single markers or in combination with established markers. Patients and Methods By applying real-time quantitative PCR, we measured the RNA expression levels of LPL, CLLU1, TCL1, MCL1 and ZAP70 in 256 newly diagnosed CLL samples from a Scandinavian population-based cohort collected from 1999 to 2002 (median follow-up, 89 months) and correlated with clinical outcome. The expression cut-offs for each RNA marker was determined by constructing ROC curves. Additionally, Binet stage, IGHV mutation status, CD38 expression (cut-off 7%) and the presence of recurrent genomic aberrations (i.e. 11q-, 17p-, 13q- and +12) were evaluated for all cases. Results High expression of all RNA-based markers except MCL1 predicted significantly shorter overall survival (OS) and time to treatment (TTT), with LPL being the most significant prognostic marker in both log-rank (Table 1) and Cox univariate regression analyses. In multivariate analysis including the RNA markers, LPL expression was the only independent prognostic factor for OS, whereas both LPL and CLLU1 could predict TTT. When including all established markers, LPL lost its significance in the model, due to its close association to the IGHV mutation status. Once the mutation status was excluded from the analysis, LPL regained its prognostic power in addition to genomic aberrations and CD38. Interestingly, all of the RNA-based markers added further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. Notably, high LPL expression predicted a worse outcome in favorable prognostic subgroups such as patients with Binet stage A, CD38 negativity or favorable genomic aberrations (Table 2). Conclusions Altogether, we conclude that LPL expression appear to be the strongest among the RNA-based markers for prediction of clinical outcome in CLL and thus could potentially be applied in the clinical laboratory to predict outcome, particularly in combination with established markers. Disclosures No relevant conflicts of interest to declare.

Download Full-text