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 < .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)

Telomere Length as a Prognostic Parameter in Chronic Lymphocytic Leukemia with Reference to IGV(H) Gene Mutation Status.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4795-4795
Author(s):  
Goran Roos ◽  
Pawel Grabowski ◽  
Magnus Hultdin ◽  
Karin Karlsson ◽  
Ulf Thunberg ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Telomere Length ◽  
Gene Mutation ◽  
Strong Association ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Prognostic Information ◽  
Mutation Status ◽  
H Gene

Abstract Recent studies on the immunoglobulin variable heavy chain (IgV(H)) genes have revealed that B-cell chronic lymphocytic leukemia (B-CLL) consists of at least 2 entities with either somatically mutated or unmutated V(H) genes. Cases with unmutated V(H) genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated V(H) genes, that is, GC experienced or post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Telomerase becomes activated during the GC reaction with an elongation of the GC-B cell telomeres and a strong association exists between V(H) gene mutation status and telomere length in CLL (ie mutated cases have longer telomeres). These results encouraged us to study telomere length and VH gene mutations in relation to clinical parameters in a large series of B-CLL cases (n=261). Telomere length was assessed by a PCR based method (Cawthon, 2002) showing very good correlation to telomere length data obtained by Southern blotting. Ig gene rearrangements were determined by DNA sequencing. The prognostic information given by the Ig mutation status (mutated vs unmutated) as well as by telomere length ("long" vs "short", cut off at median value) was statistically highly significant (p<0.0001 for both). Interestingly, the prognostic information given by telomere length seemed to be restricted to the Ig mutated CLL cases. Our data indicate that telomere length must be considered as a relevant prognostic factor of importance for B-CLL. Telomere length determination using the here applied PCR technique is fast and accurate and can easily be established in routine diagnostics.

Integrating Prognostic Markers and Cellular Signaling Identifies More Chronic Lymphocytic Leukemia Patients with Adverse Prognosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2782-2782
Author(s):  
Paul Brennan ◽  
Suhair Alghazal ◽  
Naomi Price Lloyd ◽  
Janet E. Williams ◽  
Jeff D. Griffiths ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Phosphorylation ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Training Dataset ◽  
Mutation Status ◽  
Patients At Risk ◽  
Vh Gene ◽  
Cell Signal Transduction ◽  
Time To First Treatment

Abstract In this study we devised an equation that provides a new way of identifying B-cell chronic lymphocytic leukemia (CLL) patients who will require early therapeutic intervention. The equation was developed by studying the biology of the disease with a focus on cell signal transduction. Using statistical analysis, we show that measured tyrosine phosphorylation can be described as a function of VH gene mutation status, and the expression of ZAP-70 and CD38 (r2 = 0.81, n = 49). Furthermore, we show that tyrosine phosphorylation has biological relevance as it sets a threshold for the activation of the transcription factor, NF-kB, resulting in the modulation of cell survival. Using the equation derived from our training dataset we calculated tyrosine phosphorylation in a cohort of 155 unselected CLL patient samples. The patient cohort was then divided into those with calculated tyrosine phosphorylation above or below the threshold required to activate NF-kB. Patients with high calculated tyrosine phosphorylation had a shorter time to first treatment. This method identified more patients at risk of requiring early treatment than VH gene mutation status, ZAP-70 or CD38. Furthermore, calculated tyrosine phosphorylation identifies patients that will require early intervention within the mutated VH gene cohort and even patients that have Stage A disease.

Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3807-3817 ◽  
Author(s):  
Chris Pepper ◽  
Thet Thet Lin ◽  
Guy Pratt ◽  
Saman Hewamana ◽  
Paul Brennan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Prognostic Markers ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Vh Gene

Bcl-2 family proteins play a critical role in the regulation of apoptosis in chronic lymphocytic leukemia (CLL). However, their association with established prognostic markers is unknown. In this study, we analyzed the expression of Bcl-2, Bax, and Mcl-1 in 185 CLL patients and evaluated their relationship with other prognostic markers, in vitro sensitivity to fludarabine, and clinical outcome. Mcl-1 expression was significantly correlated with stage of disease (P < .001), lymphocyte doubling time (P = .01), VH gene mutation status (P < .001), CD38 expression (P < .001), and ZAP-70 expression (P = .003). In addition, Mcl-1 and Mcl-1/Bax ratios showed strong correlations with in vitro resistance to fludarabine (P = .005 and P < .001, respectively). Furthermore, elevated Mcl-1 expression and Mcl-1/Bax ratios were predictive of time to first treatment in the whole cohort (P < .001 and P < .001, respectively) and in stage A patients only (P = .002 and P = .001, respectively). Taken together, our data show that Mcl-1 is a key controller of in vitro drug resistance and is an important regulator of disease progression and outcome in CLL. It therefore represents a promising therapeutic target in this incurable condition. The close correlation between Mcl-1 expression and VH gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis.

scholarly journals Dendritic Cells from Chronic Lymphocytic Leukemia Patients Are Normal Regardless of Ig V Gene Mutation Status

2004 ◽  
Vol 10 (7-12) ◽  
pp. 96-103 ◽  
Author(s):  
Davorka Messmer ◽  
Gloria Telusma ◽  
Tarun Wasil ◽  
Bradley T Messmer ◽  
Steven Allen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
V Gene

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

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1840-1847 ◽  
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 (&lt;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 &lt;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 &lt;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.

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.

Distinctive IgVH Gene Segments Usage and Mutation Status in Chinese Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4708-4708
Author(s):  
Lijuan Chen ◽  
Yaping Zhang ◽  
Wenjuuan Zheng ◽  
Jianyong Li ◽  
Changgeng Ruan
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Family ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Chain Gene ◽  
Mutation Status ◽  
Significant Difference ◽  
Variable Heavy ◽  
Vh Gene

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the relentless accumulation of monoclonal B cells with the appearance of small mature lymphocytes and a characteristic CD5 and CD19 co-expression immunophenotype. The incidence of CLL in Asian countries is lower than that in the Western ones, where CLL is the most common leukemia. To evaluate the frequency and mutation status of immunoglobulin (Ig) variable heavy chain gene (IgVH) expression in Chinese patients with CLL. We investigated IgVH gene segments usage and mutation status by multiplex RT-PCR in 52 CLL patients, and analyzed the relationship between IgVH somatic mutation status and the expression of CD38, ZAP-70 and CLLU1. 38 patients had mutated IgVH, and 14 had unmutated IgVH. The most frequently expressed VH gene family was found to be VH3 (46.2%) followed by VH4 (40.4%), VH1 (5.8%), VH2 (5.8%) and VH7 (1.9%), with no expression of VH5 and VH6 gene families. VH1-69 and VH3-21 which commonly overused in Western CLL weren’t detected in our cohort. The frequency of IgVH 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. IgVH gene mutation status was significantly associated with the expression of CD38 and CLLU1. The expression of them may be simple and reliable surrogates for the identification of IgVH mutations. VH gene family usage and mutation status VH family n Mutated VH gene Unmutated VH gene VH1 3 3 0 VH2 3 2 1 VH3 24 19 5 VH4 21 16 5 VH5 0 0 0 VH6 0 0 0 VH7 1 0 1

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.

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