Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia

Tobin, Gerard; Thunberg, Ulf; Karlsson, Karin; Murray, Fiona; Laurell, Anna; Willander, Kerstin; Enblad, Gunilla; Merup, Mats; Vilpo, Juhani; Juliusson, Gunnar; Sundström, Christer; Söderberg, Ola; Roos, Göran; Rosenquist, Richard

doi:10.1182/blood-2004-01-0132

Cited by 240 publications

(277 citation statements)

References 34 publications

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“…[15][16][17][18][19][20][21][22] Sequence data were analyzed using the ImMunoGeneTics database (http://imgt.cines.fr). 30,31 Sequences with a germline identity X98% were considered as unmutated, and those with an identity o98% were considered as mutated.…”

Section: Pcr Amplification Of Ig Rearrangements and Sequence Analysismentioning

confidence: 99%

“…[8][9][10] A rise in IGHV4-34 Abs is also observed in the serum of otherwise healthy individuals in response to acute infections with herpesviruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and in acute Mycoplasma pneumoniae infections. [10][11][12][13] The immunoglobulin gene repertoire expressed by chronic lymphocytic leukemia (CLL) malignant B cells is biased and notable for the existence of subsets with quasi-identical (stereotyped) B-cell receptors (BCRs), [14][15][16][17][18][19][20][21][22][23][24] implying the recognition of structurally similar epitopes, likely selecting the leukemic clones. However, the nature of the selecting antigens and their interactions with CLL progenitors or the malignant cells themselves remain shadowy.…”

Section: Introductionmentioning

confidence: 99%

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Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

et al. 2009

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The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is uniquely characterized by the presence of stereotyped B-cell receptors (BCRs). A major BCR stereotype in CLL is shared by immunoglobulin G-switched cases utilizing the immunoglobulin heavy-chain variable 4-34 (IGHV4-34) gene. Increased titers of IGHV4-34 antibodies are detected in selective clinical conditions, including infection by B-cell lymphotropic viruses, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In this context, we sought evidence for persistent activation by EBV and CMV in CLL cases expressing the IGHV4-34 gene. The study group included 93 CLL cases with an intentional bias for the IGHV4-34 gene. On the basis of real-time PCR results for CMV/EBV DNA, cases were assigned to three groups: (1) double-negative (59/93); (2) single-positive (CMV-or EBV-positive; 25/93); (3) double-positive (9/93). The doublenegative group was characterized by heterogeneous IGHV gene repertoire. In contrast, a bias for the IGHV4-34 gene was observed in the single-positive group (9/25 cases; 36%). Remarkably, all nine double-positive cases utilized the IGHV4-34 gene; seven of nine cases expressed the major BCR stereotype as described above. In conclusion, our findings indicate that the interactions of CLL progenitor cells expressing distinctive IGHV4-34 BCRs with viral antigens/superantigens might facilitate clonal expansion and, eventually, leukemic transformation. The exact type, timing and location of these interactions remain to be determined.

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Section: Pcr Amplification Of Ig Rearrangements and Sequence Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

et al. 2009

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“…2,[5][6][7][8][9][10][11] Lately, small subsets of V H 1-69 ϩ cases with more or less identical heavy-and light-chain Ig rearrangement features have also been reported. 12,13 These findings have led to the speculation that unknown antigens could be involved in the pathogenesis of V H 1-69 ϩ B-CLL.…”

Section: Introductionmentioning

confidence: 99%

Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia

Fält

Merup

Tobin

et al. 2005

Blood

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“…10 Remarkably, extensive analysis of complementarity determining regions 3 (CDR3s) of V H and V L chains has revealed that a fraction of B-CLL is characterized by a high degree of BCR homology. [12][13][14][15] As biased IgV usage and BCR homology suggest selection for a particular reactivity implicated in B-cell expansion, the recognition of these IgV features in some B-CLL groups may shed light on leukemogenesis. [4][5][6]16 Recently, we reported on a series of highly stable and indolent B-CLL patients who never required treatment over prolonged follow-up.…”

Section: Introductionmentioning

confidence: 99%

Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia

et al. 2004

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Recognition of biased immunoglobulin variable (IgV) gene usage in B-cell chronic lymphocytic leukemia (B-CLL) may yield insight into leukemogenesis and may help to refine prognostic categories. We explored Ig variable heavy (V H ) and light (V L ) chain gene usage in highly stable and indolent B-CLL (n ¼ 25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated V H 3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; Po0.01), including mutated cases (6/432; 1.39%; Po0.01) and was exceptional among indolent (1/230, 0.435%; Po0.01), and aggressive B-cell lymphomas (0/105; Po0.01). Three of six V H 3-72 B-CLL cases utilized the same V L V j 4-1 gene. Two V H 3-72 B-CLL cases had highly homologous V H complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized V j 4-1 genes with homologous IgV L CDR3s. An identical threonine to isoleucine change at codon 84 of V H 3-72 framework region 3 (FR3) recurred in four cases of highly stable V H 3-72 B-CLL. This mutation is expected to cause a conformational change of FR3 proximal to CDR3 that might critically affect high-affinity antigen binding. B-cell receptors encoded by V H 3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.

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Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia

Cited by 240 publications

References 34 publications

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia

Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia

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