Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

We performed an immunogenetic analysis of 345 IGHV --IGHD --IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; 12.8%; 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele *04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2*04 peaked at 31%. The IGHV1-2*04 rearrangements carried significantly longer complementaritydetermining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2*04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97 --99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2*04 allele.

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“…36 Among 39 functional IGHV genes identified, the most frequent by far was IGHV1-2 (86/345 rearrangements, 24. Tables 1 and 2).…”

Section: Resultsmentioning

confidence: 99%

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

et al. 2012

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“…Occasionally, CLL B-cells express more than one IGHV allele [7]. While the presence of two distinct neoplastic clones represents an obvious explanation for this phenomenon, at least in some cases there is evidence of the existence of a single clonal population expressing two distinct productive IGHV gene configurations.…”

Section: Introductionmentioning

confidence: 99%

“…Patients were considered for inclusion if they: (a) expressed two IGHV alleles; (b) were composed of one morphologically and phenotypically homogeneous B-cell population carrying one light chain (j or k), with no identifiable subpopulations or subclones according to the criteria specified in the appropriate paragraph; (c) carried two "productive" VH complementarity determining region 3 (CDR3), defined as absence of stop codons and preserved C and W anchors [7].…”

Section: Selection Of the 60 Patients With Double Ighv Definitionsmentioning

confidence: 99%

“…These cases should be distinguished from those characterized by the presence of two or more phenotypically or morphologically distinct leukemic populations (biclonal), where the double IGHV rearrangements represent either two concomitant underlying diseases or CLL subclones that generate during the course of the disease [9]. The prevalence of double IGHV expression in patients with apparently monoclonal CLL is not negligible, since it has been reported in up to 5% of the cases [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia

et al. 2013

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The immunoglobulin heavy chain variable (IGHV) gene mutational status represents a major prognostic marker in chronic lymphocytic leukemia (CLL). Usually, the prognostic implications of IGHV gene analysis can be reliably ascertained but, occasionally, double productive rearrangements have been detected. Clinical presentation and biological features of such cases are unknown. Sixty patients with morphologically and phenotypically monoclonal CLL but double productive IGHV rearrangements were retrospectively identified by mRNA analysis from three Hematology Institutions. Clinical and biological features and survival of these 60 patients were compared with a control group of patients with CLL and single IGHV rearrangement. A prospective registry was used to assess the epidemiology of double productive IGHV among incidental patients with CLL. Using standard criteria to define IGHV-mutated (M) or unmutated (U) cases, 39 of the 60 patients (65%) with double productive IGHV rearrangement had concordant status (23 MM, 16 UU), while 21 (35%) had discordant IGHV status. As compared with M patients, the MM ones had lower CD38 expression, more favorable cytogenetics and more indolent clinical behavior. Cases with UU had similar characteristics of U patients. Discordant cases presented with adverse prognostic features and had an aggressive clinical behavior requiring early treatment, similar to U patients. The prevalence of double IGHV was 3.1%. Patients with CLL with double concordant mutational status (MM or UU) have a clinical course similar to that of the corresponding single IGHV status, while those exhibiting discordant status represent a high risk population. This may help correct stratification within clinical trials. Am.

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“…ERIC, the European Research Initiative on CLL, has been at the forefront of setting standards for immunogenetic research in CLL through pioneering the adoption of good practices by: (i) arranging dedicated educational workshops for the international community; (ii) formulating recommendations for determining the SHM status of IG genes in CLL aimed at harmonizing IG gene sequence analysis in CLL in order to ensure that results are reliable and comparable among different laboratories; 24,25 (iii) establishing the IG Network, which promotes and advances immunogenetic analysis across the medical community; and (iv) launching a certification system with external quality control, an asset for accreditation of laboratories performing IG analysis.…”

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confidence: 99%

Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification

et al. 2017

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thereby provoking somatic variants characteristic of classic MDS?Although these important questions require further investigation, the work by Hirsch et al. suggests a clear distinction between MDS and other hematologic diseases with bimodal distributions. For example in aplastic anemia, it has become increasingly clear that younger patients have distinct pathophysiologies and therapeutic vulnerabilities with important clinical implications.19 However, the analysis by Hirsch et al. indicates that the molecular underpinnings of adult MDS, regardless of age, are likely more similar than they are different and that our clinical management, including enrollment in interventional studies, should reflect this.

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Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

Cited by 72 publications

References 23 publications

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia

Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification

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