Nicholas Chiorazzi

Hofstra University, Хемпстед, New York, United States

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Publications (168)1059.07 Total impact

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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is a disease in which a single B-cell clone proliferates relentlessly in peripheral lymphoid organs, bone marrow, and blood. DNA sequencing experiments have shown that about 30% of CLL patients have stereotyped antigen-specific B-cell receptors (BCRs) with a high level of sequence homology in the variable domains of the heavy and light chains. These include many of the most aggressive cases that have IGHV-unmutated BCRs whose sequences have not diverged significantly from the germ line. This suggests a personalized therapy strategy in which a toxin or immune effector function is delivered selectively to the pathogenic B cells but not to healthy B cells. To execute this strategy, serum-stable, drug-like compounds able to target the antigen-binding sites of most or all patients in a stereotyped subset are required. We demonstrate here the feasibility of this approach with the discovery of selective, high affinity ligands for CLL BCRs of the aggressive, stereotyped subset 7P that cross-react with the BCRs of several CLL patients in subset 7p, but not with BCRs from patients outside this subset.
    No preview · Article · Feb 2016 · Journal of Biological Chemistry
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    ABSTRACT: Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal prior to treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared to wildtype RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.
    No preview · Article · Dec 2015 · Blood
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is characterized by a progressive accumulation of B lymphocytes. T cell abnormalities are a common feature of CLL and contribute to impaired immune function in these patients. T cells are ineffective in eliminating the leukemic clone and may actually promote tumor growth and survival. Previous work from our laboratory documented elevated circulating levels of IL-17A-producing Th17 cells in CLL patients as compared to healthy age-matched control subjects. These high circulating Th17 levels associated with better prognostic markers and significantly longer overall survival, even among patients whose clones used unmutated IGHVs (U-CLL). Recent studies suggest that Th17 cells are heterogeneous, expressing different profiles of cytokines, and that different subsets of Th17s mediate different biological functions. In the present study, we found significantly higher levels of IL-17F-expressing CD4+ T cells in CLL versus healthy peripheral blood mononuclear cells following in vitro stimulation in the presence of Th17-promoting cytokines. Furthermore, the differentiation of IL-17F-expressing Th17 cells was significantly enhanced when purified CD4+ T cells from CLL patients were cultured in the presence of autologous CLL B cells. Lastly, single-cell network profiling revealed that IL-17F triggers NFκB phosphorylation in T and B cells from patients with CLL, but not age-matched healthy controls. Taken together, our data suggest that the phenotype of Th17 cells in CLL patients is distinct from healthy individuals, expressing higher levels of IL-17F, and that B and T cells from CLL patients are particularly responsive to IL-17F, as compared to healthy age-matched control individuals. Electronic supplementary material The online version of this article (doi:10.1007/s12026-015-8722-5) contains supplementary material, which is available to authorized users.
    Preview · Article · Oct 2015 · Immunologic Research
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    ABSTRACT: Chronic Lymphocytic Leukemia (CLL) shows a highly variable disease course, partly explained by the diverse combinations of somatic mutations whose were recently uncovered by whole-exome sequencing (WES) analysis. In physiological conditions, the enzyme Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin genes, which are necessary for an effective immune response. As a trade-off for the benefits brought about by its physiological roles, AID can also contribute to cellular transformation and tumor progression by aberrantly mutagenizing genes outside the Ig locus (off-target mutations). We previously described that progressive CLL patients aberrantly express AID in CLL B-cells of PB (Oppezzo et al., Blood 2005), and that its expression is associated with worse patient outcome (Palacios et al., Blood 2010 and Patten, et al., Blood 2012). The aims of the present work were: a) to evaluate the role of AID in CLL clonal evolution, and b) to identify AID signature mutations during disease progression. To these aims we used the transgenic Eu-TCL1 mice, a murine model that mimics a progressive and unmutated CLL disease, and crossed it with a transgenic strain overexpressing AID under the control of the actin promoter. Double transgenic actin-AID/ Eu-TCL1 mice (DT) were viable and showed no evident inborn alterations. Presence at the DNA genomic level of AID and TCL1 genes and gene expression at RNA levels was verified by quantitative PCR in PB and spleen cells, for both transgenes. DT mice expressed TCL1 and showed higher expression of AID as compared to its TCL1 counterpart, for both PB and spleen cells (n=5, p<0.05). To compare the aggressiveness of CLL disease in the DT strain with that of the Eu-TCL1 model, we chose two time points: 6 months of age as a pre-leukemic stage of the Eu-TCL1; and 10 months, in which this strain usually develops leukemia. We found that total white blood cells and percentages of leukemic IgM+CD5+ cells in PB of DT mice were increased as compared to Eu-TCL1 mice (n=15, p<0.05). DT mice also showed increased liver and spleen sizes, which were highly infiltrated with leukemic B cells. In a long-term follow up survival experiment, DT mice showed a shorter overall survival (median, 308 days) than Eu-TCL1 mice (median, 404 days, p=0.0003). Interestingly, when expression of the proliferation marker Ki-67 was evaluated in leukemic IgM+CD5+ of PB and spleen, the obtained values were higher in the DT mice at 8 to 10 months of age as compared to the Eu-TCL1 control (n=15, p<0.05 in PB; n=6, p <0.05 in spleen). We conclude that DT mice develop leukemia with more forceful kinetics and ggressiveness compared to Eu-TCL1 mice. We speculate that AID over-expression enhances CLL proliferation by mediating unknown off-target DNA mutations. Identification of AID off-target mutations associated with enhanced proliferation in this model will be evaluated by WES.
    No preview · Conference Paper · Sep 2015
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    ABSTRACT: Chronic Lymphocytic Leukemia (CLL) shows a highly variable disease course, partly explained by the diverse combinations of somatic mutations whose were recently uncovered by whole-exome sequencing (WES) analysis. In physiological conditions, the enzyme Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin genes, which are necessary for an effective immune response. As a trade-off for the benefits brought about by its physiological roles, AID can also contribute to cellular transformation and tumor progression by aberrantly mutagenizing genes outside the Ig locus (off-target mutations). We previously described that progressive CLL patients aberrantly express AID in CLL B-cells of PB (Oppezzo et al., Blood 2005), and that its expression is associated with worse patient outcome (Palacios et al., Blood 2010 and Patten, et al., Blood 2012). The aims of the present work were: a) to evaluate the role of AID in CLL clonal evolution, and b) to identify AID signature mutations during disease progression. To these aims we used the transgenic Eu-TCL1 mice, a murine model that mimics a progressive and unmutated CLL disease, and crossed it with a transgenic strain overexpressing AID under the control of the actin promoter. Double transgenic actin-AID/Eu-TCL1 mice (DT) were viable and showed no evident inborn alterations. Presence at the DNA genomic level of AID and TCL1 genes and gene expression at RNA levels was verified by quantitative PCR in PB and spleen cells, for both transgenes. DT mice expressed TCL1 and showed higher expression of AID as compared to its TCL1 counterpart, for both PB and spleen cells (n=5, p<0.05). To compare the aggressiveness of CLL disease in the DT strain with that of the Eu-TCL1 model, we chose two time points: 6 months of age as a pre-leukemic stage of the Eu-TCL1; and 10 months, in which this strain usually develops leukemia. We found that total white blood cells and ercentages of leukemic IgM CD5 cells in PB of DT mice were increased as compared to Eu-TCL1 mice (n=15, p<0.05). DT mice also showed increased liver and spleen sizes, which were highly infiltrated with leukemic B cells. In a long-term follow up survival experiment, DT mice showed a shorter overall survival (median, 308 days) than Eu-TCL1 mice (median, 404 days, p=0.0003). Interestingly, when expression of the proliferation marker Ki-67 was evaluated in leukemic IgM CD5 of PB and spleen, the obtained values were higher in the DT mice at 8 to 10 months of age as compared to the Eu-TCL1 control (n=15, p<0.05 in PB; n=6, p <0.05 in spleen). We conclude that DT mice develop leukemia with more forceful kinetics and aggressiveness compared to Eu-TCL1 mice. We speculate that AID over-expression enhances CLL proliferation by mediating unknown off-target DNA mutations. Identification of AID off-target mutations associated with enhanced proliferation in this model will be evaluated by WES. http://dx.doi.org/10.3109/10428194.2015.1080893
    Full-text · Article · Sep 2015 · Leukemia and Lymphoma
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is a clonal disease of B lymphocytes manifesting as an absolute lymphocytosis in the blood. However, not all lymphocytoses are leukemic. In addition, first-degree relatives of CLL patients have an ~15 % chance of developing a precursor condition to CLL termed monoclonal B cell lymphocytosis (MBL), and distinguishing CLL and MBL B lymphocytes from normal B cell expansions can be a challenge. Therefore, we selected FMOD, CKAP4, PIK3C2B, LEF1, PFTK1, BCL-2, and GPM6a from a set of genes significantly differentially expressed in microarray analyses that compared CLL cells with normal B lymphocytes and used these to determine whether we could discriminate CLL and MBL cells from B cells of healthy controls. Analysis with receiver operating characteristics and Bayesian relevance determination demonstrated good concordance with all panel genes. Using a random forest classifier, the seven-gene panel reliably distinguished normal polyclonal B cell populations from expression patterns occurring in pre-CLL and CLL B cell populations with an error rate of 2 %. Using Bayesian learning, the expression levels of only two genes, FMOD and PIK3C2B, correctly distinguished 100 % of CLL and MBL cases from normal polyclonal and mono/oligoclonal B lymphocytes. Thus, this study sets forth effective computational approaches that distinguish MBL/CLL from normal B lymphocytes. The findings also support the concept that MBL is a CLL precursor.
    No preview · Article · Aug 2015 · Immunologic Research
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    ABSTRACT: Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone's Ag receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated expression of TLR-9, occasional MYD88 mutations, and BCR specificity for DNA or Ags physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis after B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN+IL-15, a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this was true for B-CLL cells. Through a CFSE-based assay for quantitatively monitoring in vitro clonal proliferation/survival, we show that IL-15 precludes TLR-9-induced apoptosis and permits significant B-CLL clonal expansion regardless of the clone's BCR mutation status. A robust response to ODN+IL-15 was positively linked to presence of chromosomal anomalies (trisomy-12 or ataxia telangiectasia mutated anomaly + del13q14) and negatively linked to a very high proportion of CD38(+) cells within the blood-derived B-CLL population. Furthermore, a clone's intrinsic potential for in vitro growth correlated directly with doubling time in blood, in the case of B-CLL with Ig H chain V region-unmutated BCR and <30% CD38(+) cells in blood. Finally, in vitro high-proliferator status was statistically linked to diminished patient survival. These findings, together with immunohistochemical evidence of apoptotic cells and IL-15-producing cells proximal to B-CLL pseudofollicles in patient spleens, suggest that collaborative ODN and IL-15 signaling may promote in vivo B-CLL growth. Copyright © 2015 by The American Association of Immunologists, Inc.
    Full-text · Article · Jul 2015 · The Journal of Immunology
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    ABSTRACT: Tumor-specific metabolic changes can reveal new therapeutic targets. Our findings implicate a supporting role for fatty acid metabolism in chronic lymphocytic leukemia (CLL) cell survival. Peroxisome proliferator-activated receptor alpha (PPARα), a major transcriptional regulator of fatty acid oxidation (FAO), was recently shown to be upregulated in CLL. To evaluate PPARα as a potential therapeutic target, we have developed a highly selective, potent small molecule antagonist of PPARα, NXT629. NXT629 inhibited agonist-induced transcription of PPARα regulated genes, demonstrating target engagement in CLL cells. Furthermore, NXT629 induced apoptosis of CLL cells even in the presence of a protective microenvironment. To mimic the proliferative lymphoid compartment of CLL, we examined the activity of NXT629 on CLL cells that were stimulated to proliferate in vitro. NXT629 reduced the number of leukemia cells undergoing cell-division. In addition, in two xenograft mouse models of CLL, one a model for non-dividing and one for dividing CLL, NXT629 reduced the number of viable CLL cells in vivo. Overall, these results suggest that fatty acid metabolism promotes survival and proliferation of primary CLL cells and that inhibiting PPARα gene regulation could be a new therapeutic approach to treating CLL.
    Preview · Article · Jun 2015 · Molecular Medicine
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    Nicholas Chiorazzi
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    ABSTRACT: In this issue of Blood, Schneider et al1 document that sugar moieties, introduced into surface-membrane immunoglobulin (smIg) antigen-binding sites on follicular lymphoma (FL) cells by somatic hypermutation (SHM), induce smIg-mediated signals in a distinct, nonstandard manner. This signaling results from the sugar physically interacting with sugar-specific lectins from bacteria. The findings confirm and support the clinical relevance of previous observations about SHM introducing glycans into the variable domains of FL antigen-binding sites,2-5 and they support the potential importance of microbial exposure to lymphomagenesis and disease progression.
    Preview · Article · May 2015 · Blood
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    ABSTRACT: NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis. © 2015 Mansouri et al.
    Full-text · Article · May 2015 · Journal of Experimental Medicine

  • No preview · Article · May 2015 · Science translational medicine
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    ABSTRACT: Bispecific antibodies and antibody fragments in various formats have been explored as a means to recruit cytolytic T cells to kill tumor cells. Encouraging clinical data have been reported with molecules such as the anti-CD19/CD3 bispecific T cell engager (BiTE) blinatumomab. However, the clinical use of many reported T cell-recruiting bispecific modalities is limited by liabilities including unfavorable pharmacokinetics, potential immunogenicity, and manufacturing challenges. We describe a B cell-targeting anti-CD20/CD3 T cell-dependent bispecific antibody (CD20-TDB), which is a full-length, humanized immunoglobulin G1 molecule with near-native antibody architecture constructed using "knobs-into-holes" technology. CD20-TDB is highly active in killing CD20-expressing B cells, including primary patient leukemia and lymphoma cells both in vitro and in vivo. In cynomolgus monkeys, CD20-TDB potently depletes B cells in peripheral blood and lymphoid tissues at a single dose of 1 mg/kg while demonstrating pharmacokinetic properties similar to those of conventional monoclonal antibodies. CD20-TDB also exhibits activity in vitro and in vivo in the presence of competing CD20-targeting antibodies. These data provide rationale for the clinical testing of CD20-TDB for the treatment of CD20-expressing B cell malignancies. Copyright © 2015, American Association for the Advancement of Science.
    No preview · Article · May 2015 · Science translational medicine
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    ABSTRACT: Subset #8 is a distinctive subset of patients with chronic lymphocytic leukemia (CLL) defined by the expression of stereotyped IGHV4-39/IGKV1(D)-39 B-cell receptors. Subset #8 patients experience aggressive disease and exhibit the highest risk for Richter's transformation among all CLL. In order to obtain biological insight into this behavior, we profiled the antigen reactivity and signaling capacity of subset #8 versus other clinically aggressive stereotyped subsets, namely subsets #1 and #2. Twenty-seven monoclonal antibodies (mAbs) from subset #1, #2 and #8 CLL clones were prepared as recombinant human IgG1 and used as primary antibodies in ELISA assays against representatives of the major classes of established antigenic targets for CLL. Subset #8 CLL mAbs exhibited broad polyreactivity as they bound to all antigens tested, in clear contrast with the mAbs from the other subsets. Antigen challenge of primary CLL cells indicated that the promiscuous antigen binding activity of subset #8 mAbs can lead to significant cell activation, again contrasting the less responsive CLL cells from subsets #1 and #2 . These features constitute a distinctive profile for CLL subset #8, supporting the existence of distinct mechanisms of aggressiveness in different immunogenetic subsets of CLL. Copyright © 2015 American Society of Hematology.
    No preview · Article · Apr 2015 · Blood
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    ABSTRACT: An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL. © 2015 by The American Society of Hematology.
    No preview · Article · Jan 2015 · Blood
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    ABSTRACT: Chronic Lymphocytic Leukaemia (CLL) development and progression is thought to be driven by unknown antigens/autoantigens through the B cell receptor (BCR), and environmental signals for survival and expansion including Toll-like receptor (TLR) ligands. CD180/RP105, a membrane-associated orphan receptor of the TLR family, induces normal B cell activation and proliferation and is expressed by approximately 60% of CLL samples. Half of these respond to ligation with anti-CD180 antibody by increased activation/phosphorylation of protein kinases associated with BCR signaling. Hence CLL cells expressing both CD180 and the BCR could receive signals via both receptors. Here we investigated cross-talk between BCR and CD180-mediated signaling on CLL cell survival and apoptosis. Our data indicate that ligation of CD180 on responsive CLL cells leads to activation of either pro-survival BTK/PI3K/AKT-mediated, or pro-apoptotic p38MAPK-mediated signaling pathways, whilst sIgM ligation predominantly engages the BTK/PI3K/AKT pathway. Furthermore, pre-treatment of CLL cells with anti-CD180 redirects IgM-mediated signaling from the pro-survival BTK/PI3K/AKT towards the pro-apoptotic p38MAPK pathway. Thus pre-engaging CD180 could prevent further pro-survival signaling mediated via the BCR and, instead, induce CLL cell apoptosis, opening the door to therapeutic profiling and new strategies for the treatment of a substantial cohort of CLL patients.
    No preview · Article · Jan 2015 · Molecular Medicine

  • No preview · Conference Paper · Dec 2014

  • No preview · Conference Paper · Dec 2014
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    ABSTRACT: In patients with chronic lymphocytic leukemia (CLL), a single neoplastic antigen-specific B cell accumulates and overgrows other B cells, leading to immune deficiency. CLL is often treated with drugs that ablate all B cells, leading to further weakening of humoral immunity, and a more focused therapeutic strategy capable of targeting only the pathogenic B cells would represent a significant advance. One approach to this would be to develop synthetic surrogates of the CLL antigens allowing differentiation of the CLL cells and healthy B cells in a patient. Here, we describe nonpeptidic molecules capable of targeting antigen-specific B cell receptors with good affinity and selectivity using a combinatorial library screen. We demonstrate that our hit compounds act as synthetic antigen surrogates and recognize CLL cells and not healthy B cells. Additionally, we argue that the technology we developed can be used to identify other classes of antigen surrogates. Copyright © 2014 Elsevier Ltd. All rights reserved.
    No preview · Article · Nov 2014 · Chemistry & Biology
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    ABSTRACT: Νext generation sequencing studies in Homo sapiens have identified novel immunoglobulin heavy variable (IGHV) genes and alleles necessitating changes in the international ImMunoGeneTics information system (IMGT) GENE-DB and reference directories of IMGT/V-QUEST. In chronic lymphocytic leukaemia (CLL), the somatic hypermutation (SHM) status of the clonotypic rearranged IGHV gene is strongly associated with patient outcome. Correct determination of this parameter strictly depends on the comparison of the nucleotide sequence of the clonotypic rearranged IGHV gene with that of the closest germline counterpart. Consequently, changes in the reference directories could, in principle, affect the correct interpretation of the IGHV mutational status in CLL. To this end, we analyzed 8066 productive IG heavy chain (IGH) rearrangement sequences from our consortium both before and after the latest update of the IMGT/V-QUEST reference directory. Differences were identified in 405 cases (5 % of the cohort). In 291/405 sequences (71.9 %), changes concerned only the IGHV gene or allele name, whereas a change in the percent germline identity (%GI) was noted in 114/405 (28.1 %) sequences; in 50/114 (43.8 %) sequences, changes in the %GI led to a change in the mutational set. In conclusion, recent changes in the IMGT reference directories affected the interpretation of SHM in a sizeable number of IGH rearrangement sequences from CLL patients. This indicates that both physicians and researchers should consider a re-evaluation of IG sequence data, especially for those IGH rearrangement sequences that, up to date, have a GI close to 98 %, where caution is warranted.
    No preview · Article · Nov 2014 · Immunogenetics

  • No preview · Article · Oct 2014 · Cancer Research

Publication Stats

7k Citations
1,059.07 Total Impact Points

Institutions

  • 2013-2015
    • Hofstra University
      Хемпстед, New York, United States
  • 2004-2015
    • The Feinstein Institute for Medical Research
      • Laboratory of Experimental Rheumatology
      New York, New York, United States
  • 2002-2015
    • Hofstra North Shore-LIJ School of Medicine
      New York, New York, United States
    • Bielefeld University
      Bielefeld, North Rhine-Westphalia, Germany
  • 2001-2015
    • North Shore-Long Island Jewish Health System
      New York, New York, United States
  • 2006-2011
    • Albert Einstein College of Medicine
      • • Department of Cell Biology
      • • Department of Medicine
      New York, New York, United States
  • 1999-2008
    • NYU Langone Medical Center
      • Department of Medicine
      New York, New York, United States
  • 2003-2006
    • North Shore-LIJ Health System
      Manhasset, New York, United States
  • 2005
    • CUNY Graduate Center
      New York, New York, United States
  • 2000
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1994
    • Weill Cornell Medical College
      • Department of Medicine
      New York, New York, United States
  • 1989-1992
    • Cornell University
      • Department of Medicine
      Ithaca, New York, United States