Reading the B-cell receptor immunome in chronic lymphocytic leukemia: revelations and applications

Hengeveld, Paul J.; Levin, Mark‐David; Kolijn, P. Martijn; Langerak, Anton W.

doi:10.1016/j.exphem.2020.09.194

Cited by 10 publications

(8 citation statements)

References 79 publications

(75 reference statements)

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“…Although CLL is generally of monoclonal origin, multiple productive IGH rearrangements have been observed in around 2% of CLL cases (16). These can arise from a single CLL clone (biallelic rearrangement) or reflect biclonal CLL disease (41,42). Interestingly, family member 1D appeared to have biclonal CLL consisting of a SmIgk+ and a SmIgl+ CLL clone as determined by flow cytometry (data not shown).…”

Section: Familial Cll Shows Consistent Bcr Ig Characteristicsmentioning

confidence: 86%

Consistent B Cell Receptor Immunoglobulin Features Between Siblings in Familial Chronic Lymphocytic Leukemia

et al. 2021

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Key processes in the onset and evolution of chronic lymphocytic leukemia (CLL) are thought to include chronic (antigenic) activation of mature B cells through the B cell receptor (BcR), signals from the microenvironment, and acquisition of genetic alterations. Here we describe three families in which two or more siblings were affected by CLL. We investigated whether there are immunogenetic similarities in the leukemia-specific immunoglobulin heavy (IGH) and light (IGL/IGK) chain gene rearrangements of the siblings in each family. Furthermore, we performed array analysis to study if similarities in CLL-associated chromosomal aberrations are present within each family and screened for somatic mutations using paired tumor/normal whole-genome sequencing (WGS). In two families a consistent IGHV gene mutational status (one IGHV-unmutated, one IGHV-mutated) was observed. Intriguingly, the third family with four affected siblings was characterized by usage of the lambda IGLV3-21 gene, with the hallmark R110 mutation of the recently described clinically aggressive IGLV3-21R110 subset. In this family, the CLL-specific rearrangements in two siblings could be assigned to either stereotyped subset #2 or the immunogenetically related subset #169, both of which belong to the broader IGLV3-21R110 subgroup. Consistent patterns of cytogenetic aberrations were encountered in all three families. Furthermore, the CLL clones carried somatic mutations previously associated with IGHV mutational status, cytogenetic aberrations and stereotyped subsets, respectively. From these findings, we conclude that similarities in immunogenetic characteristics in familial CLL, in combination with genetic aberrations acquired, point towards shared underlying mechanisms behind CLL development within each family.

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Section: Familial Cll Shows Consistent Bcr Ig Characteristicsmentioning

confidence: 86%

Consistent B Cell Receptor Immunoglobulin Features Between Siblings in Familial Chronic Lymphocytic Leukemia

et al. 2021

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“…S8 ). Although true bi- or oligoclonality is an infrequent phenomenon in B-cell lymphoproliferative disorders 37 , 38 , biclonality has been reported mostly in the context of composite lymphomas 39 – 41 , and also within single lymphoma subtypes 42 , 43 and in immunosuppressed patients 44 , 45 . It is known that, especially in patients with a history of infectious mononucleosis or immune deficiencies, EBV latent antigens can regulate or mimic different survival and proliferative signaling pathways, and thereby promote lymphomagenesis 46 – 48 .…”

Section: Discussionmentioning

confidence: 99%

Clonality assessment and detection of clonal diversity in classic Hodgkin lymphoma by next-generation sequencing of immunoglobulin gene rearrangements

et al. 2022

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Clonality analysis in classic Hodgkin lymphoma (cHL) is of added value for correctly diagnosing patients with atypical presentation or histology reminiscent of T cell lymphoma, and for establishing the clonal relationship in patients with recurrent disease. However, such analysis has been hampered by the sparsity of malignant Hodgkin and Reed-Sternberg (HRS) cells in a background of reactive immune cells. Recently, the EuroClonality-NGS Working Group developed a novel next-generation sequencing (NGS)-based assay and bioinformatics platform (ARResT/Interrogate) to detect immunoglobulin (IG) gene rearrangements for clonality testing in B-cell lymphoproliferations. Here, we demonstrate the improved performance of IG-NGS compared to conventional BIOMED-2/EuroClonality analysis to detect clonal gene rearrangements in 16 well-characterized primary cHL cases within the IG heavy chain (IGH) and kappa light chain (IGK) loci. This was most obvious in formalin-fixed paraffin-embedded (FFPE) tissue specimens, where three times more clonal cases were detected with IG-NGS (9 cases) compared to BIOMED-2 (3 cases). In total, almost four times more clonal rearrangements were detected in FFPE with IG-NGS (N = 23) as compared to BIOMED-2/EuroClonality (N = 6) as judged on identical IGH and IGK targets. The same clonal rearrangements were also identified in paired fresh frozen cHL samples. To validate the neoplastic origin of the detected clonotypes, IG-NGS clonality analysis was performed on isolated HRS cells, demonstrating identical clonotypes as detected in cHL whole-tissue specimens. Interestingly, IG-NGS and HRS single-cell analysis after DEPArray™ digital sorting revealed rearrangement patterns and copy number variation profiles indicating clonal diversity and intratumoral heterogeneity in cHL. Our data demonstrate improved performance of NGS-based detection of IG gene rearrangements in cHL whole-tissue specimens, providing a sensitive molecular diagnostic assay for clonality assessment in Hodgkin lymphoma.

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“…Several studies have shown reliable detection of MRD down to 10 À6 by NGS. 45,46 In ALL, NGS has been cited to be more accurate than current universal methods, including PCR. 47 In another study with 378 samples spanning ALL, MM, and MCL, there was good correlation between PCR and NGS MRD (R ¼ 0.8; P , .001); furthermore, NGS had at least the same degree of sensitivity as PCR without the need for patient-specific primers.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Clonotypic Rearrangements and Minimal Residual Disease in Lymphoid Malignancies

Hussaini

Srivastava

Lee

et al. 2021

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been incorporated into consensus criteria regarding treatment response, strategy, and clinical trial endpoints. clonoSEQ (a next-generation sequencing [NGS]-MRD assay) uses multiplex polymerase chain reaction and NGS to identify clonotypic rearrangements at the immunoglobulin (Ig) H, IgK, IgL, T-cell receptor (TCR)-β, and TCR-γ loci, and translocated B-cell lymphoma 1/IgH and 2/IgH sequences for MRD assessment. Additionally, it can be used to confirm diagnoses of cutaneous T-cell lymphoma (CTCL). Objective.— To review the technical aspects of our experience using the clonoSEQ Assay in routine clinical practice. Design.— In this single-center experience, 390 patients with lymphoid and plasma cell malignancies were assessed with the NGS-MRD Assay at a central laboratory. Results.— Median time from arrival of the shipment to initiation of the assay (defined as captured in Adaptive's secure tracking system) was 2.1 hours. Overall, 317 patients had 1 or more samples submitted for sequence identification. Of these, 290 (91.5%) had trackable sequences identified. The median calibration rate of samples by malignancy (where n ≥ 10 samples, excluding CTCL samples) was 88.1%, across a variety of fresh and archived sample sources (177 of 201 samples). TCR-β and/or TCR-γ clonotypes were identified in 40 of 95 samples (42.1%) from 66 patients with suspected CTCL. Conclusions.— This NGS-MRD Assay is a valuable and sensitive tool for monitoring MRD in patients with plasma cell and lymphoid malignancies and assisting in the diagnosis of CTCL.

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Reading the B-cell receptor immunome in chronic lymphocytic leukemia: revelations and applications

Cited by 10 publications

References 79 publications

Consistent B Cell Receptor Immunoglobulin Features Between Siblings in Familial Chronic Lymphocytic Leukemia

Consistent B Cell Receptor Immunoglobulin Features Between Siblings in Familial Chronic Lymphocytic Leukemia

Clonality assessment and detection of clonal diversity in classic Hodgkin lymphoma by next-generation sequencing of immunoglobulin gene rearrangements

Assessment of Clonotypic Rearrangements and Minimal Residual Disease in Lymphoid Malignancies

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