The Immunoglobulin genes and Chronic Lymphocytic Leukemia (CLL)

Tobin, Gerard

doi:10.3109/2000-1967-075

Cited by 11 publications

(14 citation statements)

References 87 publications

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“…If the development of the malignant CLL clone occurred independently of antigenic interaction, one would expect the gene usage and CDR3 sequences (the most individual antigen-binding part of the immunoglobulin) of CLL BCRs to be randomly distributed as in normal B-cells. However, the CLL immunoglobulin gene usage is biased [22], [23], [24], [25] and a number of highly similar CDR3 regions are expressed. Indeed, more than 26% of CLL cells express BCRs belonging to one of almost 150 stereotyped subsets with virtually identical CDR3 sequences characterized so far [19], [20], [24], [26], [27], [28].…”

Section: Introductionmentioning

confidence: 99%

Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells

et al. 2010

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as “subset 1”) recognize antigens highly expressed in stromal cells – vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20–45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease.

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Section: Introductionmentioning

confidence: 99%

Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells

et al. 2010

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“…Tobin et al 12 initially reported that patients with CLL cells that express IGHV3-21 have relatively aggressive disease, even when the expressed IGHV3-21 had evidence for somatic mutation. 13,14 However, such mutated (M) IGHV3-21 frequently had higher percent homology to the germline IGHV3-21 (eg, Ͼ 97%) than did the M-IGHV of other CLL cases that do not use IGHV3-21, which on average have less than 94% homology to any known germline IGHV gene. 3,4,15 This led to speculation that there might be genetic polymorphism in IGHV3-21 and that use of different IGHV3-21 alleles only gave the appearance that such Ig had undergone somatic mutation.…”

mentioning

confidence: 99%

“…16 However, Tobin et al 14 analyzed the germline IGHV3-21 genes of patients with CLL cells that used M-IGHV3-21 and found that genetic polymorphism could not account for the base substitutions observed in the expressed IGHV3-21 genes, indicating that they indeed had incurred somatic mutations. 13,14 However, it still was is not resolved whether CLL cells expressing such M-IGHV3-21 were derived from B cells that had experienced maturation in the germinal center, where B cells can undergo Ig somatic hypermutation during the immune response to antigen.Furthermore, the prevalence of CLL cases that use IGHV3-21 in the United States is uncertain. Although initially reported that 31 of 265 patients in a Scandinavian study had CLL cells that used IGHV3-21 (12%), more recent studies of patients mostly from southern and central Europe found that less than 3% of all patients used this IGHV.…”

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confidence: 99%

Use of IGHV3–21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post–germinal center leukemogenic selection

Ghia¹,

Jain

Widhopf³

et al. 2008

Blood

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We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.

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“…Furthermore, progressive disease can be predicted using a combination of cellular markers including Zap-70 [3 -6] and CD38 expression [2,7,8] or by gene expression profiling of lipoprotein lipase (LPL) and CLLU-1 [9,10]. In addition, it is becoming increasingly clear that IgHV gene usage, associated with or independent of mutational status, may be of prognostic significance [11].…”

Section: Introductionmentioning

confidence: 99%

Mutated IgHV1-69 gene usage represents a distinct subgroup associated with indolent disease in chronic lymphocytic leukemia

Galligan

Catherwood

Matthews

et al. 2008

Leukemia & Lymphoma

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Biased IgHV gene usage in chronic lymphocytic leukemia (CLL) is well documented and suggests antigen involvement in leukemogenesis. IgHV1-69 is one of the most frequently rearranged IgHV genes in CLL and the majority of IgHV1-69 cases lack somatic hypermutation and display poor prognosis. However, its independent prognostic impact remains uncertain given reports showing a low proportion of mutated IgHV1-69 cases and stereotyped IgHV1-69 subsets with divergent clinical outcome. We assessed the frequency and clinical significance of IgHV1-69 gene usage in a cohort of 330 CLL patients. Functional IgHV1-69 gene rearrangements were detected in 32 cases (9.7%), 31 of which were characterised further. Seven (22.6%) were found to have undergone somatic hypermutation. This subgroup had shorter and more diverse complementarity determining region 3 (CDR3) sequences compared with unmutated IgHV1-69 cases. In addition, mutated IgHV1-69 gene status was associated with lower cell surface CD38 expression and less progressive disease as monitored by Binet staging, lymphocyte doubling time and requirement of chemotherapeutic intervention. To conclude, we present data confirming that IgHV1-69 gene rearrangements in CLL are not exclusively associated with unmutated IgHV status. In addition, we show that a somatically hypermutated subgroup may demonstrate more indolent characteristics despite the general association of IgHV1-69 gene usage with aggressive disease.

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The Immunoglobulin genes and Chronic Lymphocytic Leukemia (CLL)

Cited by 11 publications

References 87 publications

Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells

Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells

Use of IGHV3–21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post–germinal center leukemogenic selection

Mutated IgHV1-69 gene usage represents a distinct subgroup associated with indolent disease in chronic lymphocytic leukemia

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