Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients

Tschumper, Renee C.; Geyer, Susan; Campbell, Megan E.; Kay, Neil E.; Shanafelt, Tait D.; Zent, Clive S.; Nowakowski, Grzegorz S.; Call, Timothy G.; Dewald, Gordon W.; Jelinek, Diane F.

doi:10.1172/jci32625

Cited by 21 publications

(23 citation statements)

References 61 publications

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“…All the reported variables were proven to be significant predictors for TTT (Supplementary Table S2 and Fig. S2), in keeping with our previous studies and those of other groups (1,7,12,27,36 Table S2 and Fig. 2).…”

Section: Resultssupporting

confidence: 88%

Expression of Mutated IGHV3-23 Genes in Chronic Lymphocytic Leukemia Identifies a Disease Subset with Peculiar Clinical and Biological Features

Bomben

Benedetti

et al. 2010

Clinical Cancer Research

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Purpose: B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease whose outcome can be foreseen by investigating the mutational status of immunoglobulin heavy chain variable (IGHV) genes. Moreover, a different prognosis was reported for CLL expressing specific IGHV genes in the context or not of stereotyped B-cell receptors. Here we investigated novel associations between usage of specific IGHV genes and clinical features in CLL.Experimental Design: Among 1,426 CLL-specific IG-rearrangements, stereotyped B-cell receptor clusters never utilized the IGHV3-23 gene. Given this notion, this study was aimed at characterizing the IGHV3-23 gene in CLL, and identifying the properties of IGHV3-23-expressing CLL.Results: IGHV3-23 was the second most frequently used (134 of 1,426) and usually mutated (M; 109 of 134) IGHV gene in our CLL series. In the vast majority of M IGHV3-23 sequences, the configuration of the 13 amino acids involved in superantigen recognition was consistent with superantigen binding. Clinically, M IGHV3-23 CLL had shorter time-to-treatment than other M non-IGHV3-23 CLL, and multivariate analyses selected IGHV3-23 gene usage, Rai staging, and chromosomal abnormalities as independent prognosticators for M CLL. Compared with M non-IGHV3-23 CLL, the gene expression profile of M IGHV3-23 CLL was deprived in genes, including the growth/tumor suppressor genes PDCD4, TIA1, and RASSF5, whose downregulation is under control of miR-15a and miR-16-1. Accordingly, relatively higher levels of miR-15a and miR-16-1 were found in M IGHV3-23 compared with M non-IGHV3-23 CLL.Conclusions: Altogether, expression of the IGHV3-23 gene characterizes a CLL subset with distinct clinical and biological features. Clin Cancer Res; 16(2); 620-8. ©2010 AACR.Chronic lymphocytic leukemia (CLL) is a heterogeneous disease whose clinical course can be foreseen by the presence of mutated (M) or unmutated (UM) immunoglobulin heavy chain variable (IGHV) genes (1). Although CLL with UM IGHV genes usually has a worse prognosis, great heterogeneity is still documented in the context of CLL subgroups expressing either UM or M IGHV genes (1).Analyses of IGHV gene usage has revealed a biased repertoire occurring in CLL versus normal B cells, and in UM versus M CLL (1, 2). Moreover, a discrete fraction of CLL expresses stereotyped combinations of IGHV genes, complementarity-determining region-3 (HCDR3), and IGV light chains (3-7). These observations, coupled with an IGHV mutation profile often consistent with antigen-driven

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Section: Resultssupporting

confidence: 88%

Expression of Mutated IGHV3-23 Genes in Chronic Lymphocytic Leukemia Identifies a Disease Subset with Peculiar Clinical and Biological Features

Bomben

Benedetti

et al. 2010

Clinical Cancer Research

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“…Accordingly, investigators worldwide have frequently used other end points such as time to first treatment (TTFT) as a surrogate for disease aggressiveness. [7][8][9][10] Most investigators calculate TTFT using the inverse of a KM (1-KM) plot, but a problem arises in those patients who die before requiring any therapy. Since KM estimates only consider one possible event, the only option remaining is to censor these patients at the time of death, and this is never adequate.…”

Section: Roc Curves Versus Maximally Selected Rank Statisticsmentioning

confidence: 99%

Survival analysis in hematologic malignancies: recommendations for clinicians

et al. 2014

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The widespread availability of statistical packages has undoubtedly helped hematologists worldwide in the analysis of their data, but has also led to the inappropriate use of statistical methods. In this article, we review some basic concepts of survival analysis and also make recommendations about how and when to perform each particular test using SPSS, Stata and R. In particular, we describe a simple way of defining cut-off points for continuous variables and the appropriate and inappropriate uses of the Kaplan-Meier method and Cox proportional hazard regression models. We also provide practical advice on how to check the proportional hazards assumption and briefly review the role of relative survival and multiple imputation. ABSTRACTclassification does not exist in real life.An interesting alternative is provided by maximally selected rank statistics.2 This test can be easily applied using R (maxstat package) and has several advantages. First, there is no need to transform the time-dependent end point. Second, the test calculates an exact cut-off point, which can be estimated using several methods and approximations, and the discrimination power is also evaluated and estimated with a P value (type I error). Once you get the exact value (e.g. 2.3 mg/L), it is important to see if it is clinically relevant. For instance, in our institution, the upper limit of normality (ULN) for b2M is 2.4 mg/L, and we therefore decided to use 2.4 instead of 2.3 in order to avoid over-fitting the data. The idea behind this concept is that the investigator should look for a value that is clinically relevant (e.g. ULN, 2xULN, 3xULN) and easily applicable to a different patient population, and not the cut-off point that best describes the investigator's own patient cohort. Kaplan-Meier versus cumulative incidence curvesKaplan-Meier (KM) estimates are commonly used for survival analysis and identification of prognostic factors, and the reason is that it is possible to analyze patients irrespective of their follow up.

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“…As previously shown for productive rearrangements in CLL (32,33), this gene is preferentially used in RF2, thus encoding for a relatively long peptide sequence (10 amino acids: YYDFWSGYYT) with a predicted acidic isoelectric point value (3.8). Additionally, rearrangements carrying the IGHD3-3 gene are biased to the usage of the IGHJ6 gene (YYYYYGMDV) (32,33), leading to the formation of long VH CDR3 enriched in tyrosine residues (Figure 2). In principle, increased usage of any single amino acid restricts the overall VH CDR3 variability (34).…”

Section: Table 2 Tdt and Exonuclease Activity In Productively Rearramentioning

confidence: 68%

“…However, tyrosine may be considered as an exception in that it allows for many forms of inter-and intramolecular bonding that enable aromatic stacking interactions and, thus, increase VH CDR3 flexibility and, likely, the range of antigenic epitopes that can be "accommodated" in the antigen-binding loop (34). Interestingly, usage of IGHD3-3 in RF2 among V-D-J, especially those using the IGHV1-69 gene, has been reported as an adverse prognostic indicator in CLL (32).…”

Section: Table 2 Tdt and Exonuclease Activity In Productively Rearramentioning

confidence: 99%

Partial versus Productive Immunoglobulin Heavy Locus Rearrangements in Chronic Lymphocytic Leukemia: Implications for B-Cell Receptor Stereotypy

Tsakou

Agathagelidis

Boudjoghra

et al. 2011

Mol Med

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The frequent occurrence of stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences among unrelated cases with chronic lymphocytic leukemia (CLL) is widely taken as evidence for antigen selection. Stereotyped VH CDR3 sequences are often defined by the selective association of certain immunoglobulin heavy diversity (IGHD) genes in specific reading frames with certain immunoglobulin heavy joining (IGHJ ) genes. To gain insight into the mechanisms underlying VH CDR3 restrictions and also determine the developmental stage when restrictions in VH CDR3 are imposed, we analyzed partial IGHD-IGHJ rearrangements (D-J) in 829 CLL cases and compared the productively rearranged D-J joints (that is, in-frame junctions without junctional stop codons) to (a) the productive immunoglobulin heavy variable (

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Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients

Cited by 21 publications

References 61 publications

Expression of Mutated IGHV3-23 Genes in Chronic Lymphocytic Leukemia Identifies a Disease Subset with Peculiar Clinical and Biological Features

Expression of Mutated IGHV3-23 Genes in Chronic Lymphocytic Leukemia Identifies a Disease Subset with Peculiar Clinical and Biological Features

Survival analysis in hematologic malignancies: recommendations for clinicians

Partial versus Productive Immunoglobulin Heavy Locus Rearrangements in Chronic Lymphocytic Leukemia: Implications for B-Cell Receptor Stereotypy

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