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

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2246-2252 ◽  
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.

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

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1178-1178
Author(s):  
Alexander Kröber ◽  
Pawel Grabowski ◽  
Andreas Bühler ◽  
Till Seiler ◽  
Hartmut Döhner ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Survival Probability ◽  
Inverse Correlation ◽  
Single Copy ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Genomic Aberrations

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&lt;0.001), 2. CD38 expression (r=−0.44, p&lt;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&lt;0.001) and cases with two or more genomic aberrations (26 vs. 6%, p&lt;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.

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

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1410-1416 ◽  
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 &lt;.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.

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

2006 ◽  
Vol 24 (6) ◽  
pp. 969-975 ◽  
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.

Research on the Characteristics of IGHV Gene In Chronic Lymphocytic Leukemia of China.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4609-4609
Author(s):  
Chun Qiao ◽  
Kourong Miao ◽  
Jianyong Li
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Ighv Gene ◽  
Significant Difference

Abstract Abstract 4609 Objective The usage, mutation status and prognostic impact of immunoglobulin heavy chain variable (IGHV) gene in Chinese patients with chronic lymphocytic leukemia (CLL) is unclear. We set out to define the characteristics of IGHV gene and its relevance to clinical and biological parameter in our patients. Methods IGHV gene mutations were detected by multiplex PCR in 202 Chinese CLL patients and the purified PCR amplification products were sequenced. IGHV somatic hypermutation status and gene usage were analyzed by IMGT/V-QUEST software. The association analysis between IGHV somatic mutation status and the clinical and biological features, including Binet staging, immunophenotype, cytogenetic aberrant, were also emphasized in this study. Results The results showed that 129 patients had mutated (M) IGHV, and the remaining 73 patients had unmutated (UM) IGHV according to the cutoff value of accordance rate 98%. The most frequent VH gene family was found to be VH3 (47.5%), followed by VH4 (34.7%), VH1 (11.4%), VH2 (2.5%), VH5(1.5%), VH7(1.5%) and VH6(0.9%) gene families, which was similar to other Asian populations. The overall survival (OS) time of UM IGHV group was significant shorter than M IGHV group (P=0.025). Significance was found in the expression of CD38 and ZAP-70 between patients with and without IGHV mutations (P<0.0001 and P=0.015, respectively). Binet staging was significantly different with IGHV mutation status (P<0.001). “Unmutated” sequences had significantly longer heavy chain complementarity-determining region 3 (HCDR3). Seven of these patients used VH1-69, which was similar to other Asia countries, but in striking contrast to those in Western countries, where VH1-69 was one of the most frequently used genes. FISH was performed in 117 cases, del(11q22) was considered as high risk factors, and 10(10/42, 23.8%) cases with UM IGHV gene. On the other hand, there were 7(7/75, 9.3%) cases with M IGHV gene (P=0.033). No significance was found in del(17p),del(13q),del(6q),add(12),IGH translocation between IGHV mutation and unmuatioan patients. A total of five stereotyped BCR were identified, IGHV3-21/IGHD3-9/IGHJ6, IGHV4-34/IGHD2-15/IGHJ6, IGHV1-3/IGHD6-19/IGHJ4, IGHV4-59/IGHD3-22/IGHJ6 and IGHV4-39/IGHD6-13/IGHJ5. Conclusions The usage of IGHV gene families indicates significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. In the development course of CLL, BCR play an important role in the immunological recognition and selection. There are intimate relationships between mutation status of IGHV gene and prognosis. The usage of IGHV provides enlightment for the occurrence mechanism of CLL. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4807-4812 ◽  
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 &lt; .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P &lt; .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 &lt; .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)

The Prognostic Significance of Positive Direct Antiglobulin Test in Chinese Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4183-4183
Author(s):  
Wei Xu ◽  
Jianyong Li ◽  
Xin Cao ◽  
DAN-Xia Zhu ◽  
Lin Yao ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Direct Antiglobulin Test ◽  
Chinese Patients ◽  
Prognostic Impact ◽  
Antiglobulin Test ◽  
Positive Direct

Abstract Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemias in the Western countries, however, infrequent in the Eastern. Autoimmune hemolytic anemia (AHA) is a complication in chronic lymphocytic leukemia (CLL). The direct antiglobulin test (DAT) may be positive at some time during the disease course in up to 35% of cases, but overt AHA occurs less frequently. The aim of the study was to explore the prognostic impact of positive DAT in Chinese patients with CLL and its correlation with other prognostic factors, including Binet stages, lymphocyte count in peripheral blood, lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), IgVH mutation status, ZAP-70, CD38 and cytogenetic abnormalities. Out of the 80 Chinese patients with CLL, positive DAT was found in 21 (30.6%) cases. The incidence of positive was 12.5% in Binet A, 23.8% and 44.4% in Binet B and C, respectively. The incidence of positive DAT was significantly increased at Binet C, compared with Binet A (P=0.006), and the presence of higher LDH and β2-MG levels correlated strongly with positive DAT (P=0.006 and P=0.004, respectively). Patients with unmutated IgVH genes had higher incidence of positive DAT than did patients with IgVH mutations (P=0.042), and positive DAT was also associated with higher level of ZAP-70 and CD38 (P=0.004 and P&lt;0.001, respectively). We also analyzed positive DAT in different cytogenetic subgroups. Higher incidence of positive DAT was found in patients with unfavorable cytogenetic aberrations (deletion in 17p13 or 11q22) in contrast to lower level in good risk cytogenetics (deletion in 13q as the sole abnormality) (P = 0.002). Positive DAT was associated with poor outcome. Survival analysis showed that the patients with positive DAT had significantly shorter OS (mean, 106.3 months) (95% CI, 74.7 to 137.8 months) than the patients negative DAT (mean, 151.5 months) (95% CI, 122.3 to 180.6 months) (P=0.024). Patients treated with fludarabine were not likely to remain DAT positive and to change from negative to positive (P=0.209). In conclusion, DAT status provides a new prognostic indicator and correlates with other clinical or laboratory prognostic factors, and might be applied for the assessment of prognosis in patients with CLL.

scholarly journals IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load

Haematologica ◽  
2021 ◽  
pp. 0-0
Author(s):  
Dianna Hussmann ◽  
Anna Starnawska ◽  
Louise Kristensen ◽  
Iben Daugaard ◽  
Astrid Thomsen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcomes ◽  
Lymphocytic Leukemia ◽  
Mutation Load ◽  
450K Array ◽  
Mutation Status ◽  
Classification Procedure ◽  
Array Data ◽  
Ighv Gene ◽  
Classification Procedures

Currently, no molecular biomarker indexes are used in standard care to make treatment decisions at diagnosis of chronic lymphocytic leukemia (CLL). We used Infinium MethylationEPIC array data from diagnostic blood samples of 114 CLL patients, and developed a patient stratification procedure based on methylation signatures associated with mutation load of the IGHV gene. This procedure allowed us to predict the time to treatment (TTT) with HR 8.34 (95% CI, 4.54-15.30), as opposed to HR 4.35 (95% CI, 2.60-7.28) for IGHV mutation status. Detailed evaluation of 17 discrepant cases between the two classification procedures showed that these cases were incorrectly classified using IGHV status. Moreover, methylation-based classification stratified patients with different overall survival (OS) (HR, 1.82; 95% CI, 1.07-3.09), which was not possible using IGHV status. Furthermore, we assessed the performance of the developed classification procedure using published HumanMethylation450 array data for 159 patients for which TTT, OS and relapse were available. Despite that 450K array methylation data did not contain all biomarkers used in our classification procedure, methylation signatures again stratified patients with significantly better accuracy than IGHV mutation load regarding all available clinical outcomes. Thus, stratification using IGHV-associated methylation signatures may provide improved prognostic power than IGHV mutation status.

scholarly journals Karyotype-specific microRNA signature in chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3872-3879 ◽  
Author(s):  
Rosa Visone ◽  
Laura Z. Rassenti ◽  
Angelo Veronese ◽  
Cristian Taccioli ◽  
Stefan Costinean ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Abnormalities ◽  
Variable Region ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Mutation Status ◽  
Ighv Gene ◽  
Trisomy 12 ◽  
Disease Initiation

Abstract Chromosomal abnormalities, immunoglobulin heavy chain variable–region (IGHV) gene mutation status, and ζ-associated protein 70 (ZAP-70) expression levels have independent prognostic relevance in chronic lymphocytic leukemia (CLL); however, their concordance is variable. Because deregulation of microRNAs has been linked to disease initiation and progression in CLL, we studied the value of the microRNAs as a signature for CLL patients with specific chromosomal abnormalities. We identified 32 microRNAs able to discriminate the 11q deletion, 17p deletion, trisomy 12, 13q deletion, and normal karyotype cytogenetic subgroups. The expression values of 9 among the 32 microRNAs (miR-151-3p, miR-34a, miR-29c, miR-29b, miR-155, miR-148a, miR-146a, miR-146b5p, and miR-640) were correlated with gene expression data from the same samples to assess their biologic impact on CLL. In this study we also found that IGHV unmutated, high expression of ZAP-70 protein, and low expression of the miR-223, miR-29c, miR-29b, and miR-181 family were strongly associated with disease progression in CLL cases harboring 17p deletion, whereas in those harboring trisomy 12 only high expression of the miR-181a, among the analyzed parameters, suggested more aggressive disease. Thus, the use of the microRNA-based classifications may yield clinically useful biomarkers of tumor behavior in CLL.

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

2002 ◽  
Vol 26 (9) ◽  
pp. 791-794 ◽  
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

scholarly journals CD200 Baseline Serum Levels Predict Prognosis of Chronic Lymphocytic Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4239
Author(s):  
Giovanni D’Arena ◽  
Candida Vitale ◽  
Marta Coscia ◽  
Daniela Lamorte ◽  
Giuseppe Pietrantuono ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Serum Levels ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Baseline Serum ◽  
Response To Chemotherapy ◽  
Relevant Role ◽  
Time To First Treatment

Membrane-bound CD200 is overexpressed in chronic lymphocytic leukemia (CLL), and there is some evidence that its soluble ectodomain (sCD200) could also be involved in the pathophysiology and the disease. However, very little is known about sCD200’s prognostic significance. sCD200 was tested at diagnosis in 272 patients with CLL and in 78 age- and sex-matched healthy subjects using a specific human CD200 (OX-2 membrane glycoprotein) ELISA kit. A significantly higher concentration of sCD200 was found in CLL patients compared to controls. In our cohort, sCD200 was significantly higher in patients who were older than 66 years, with Binet stage C, unmutated IgVH and unfavorable (del11q or del17p) FISH. Time-to-first treatment and overall survival were significantly shorter in patients with higher sCD200 concentration, using as a cut-off 1281 pg/mL, the median value for sCD200 concentration in the whole CLL cohort. However, the prognostic impact of sCD200 was not confirmed in multivariate analysis. Baseline sCD200 values appeared to have an impact on the response to chemotherapy or chemo-immunotherapy, but not to targeted agents. Collectively, our data show that sCD200 serum levels correlate with more aggressive clinical and biological features and are able to predict a worse prognosis. This work supports the relevant role of CD200 not only as a diagnostic tool but also as a prognostic indicator and a potential therapeutic target in CLL.

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