Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1848-1854 ◽  
Author(s):  
Terry J. Hamblin ◽  
Zadie Davis ◽  
Anne Gardiner ◽  
David G. Oscier ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Trisomy 12 ◽  
Vh Gene ◽  
Vh Genes ◽  
Variable Region Genes

Abstract Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.

Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1848-1854 ◽  
Author(s):  
Terry J. Hamblin ◽  
Zadie Davis ◽  
Anne Gardiner ◽  
David G. Oscier ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Trisomy 12 ◽  
Vh Gene ◽  
Vh Genes ◽  
Variable Region Genes

Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.

Somatic mutation of bcl-6 genes can occur in the absence of VH mutations in chronic lymphocytic leukemia

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3534-3540 ◽  
Author(s):  
Surinder S. Sahota ◽  
Zadie Davis ◽  
Terry J. Hamblin ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
V Genes ◽  
History Of ◽  
Vh Genes ◽  
V Region

Somatic mutation in immunoglobulin variable (V) region genes occurs largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the cell of origin. Recently, it has been found that chronic lymphocytic leukemia (CLL) consists of 2 subsets, each with a different clinical course, one with unmutated VH genes consistent with a naive B cell, and the other with mutated VH genes consistent with transit through the germinal center. However, somatic mutation also occurs at another distinct locus, the 5′ noncoding region of thebcl-6 gene, in both B-cell tumors and in normal germinal center B cells. To probe the suggestive link between the occurrence of mutations in VH and bcl-6 genes, we analyzed the nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated VH genes, with 4 of 10 cases clearly showing mutations inbcl-6. In those CLLs defined by somatically mutated VH genes, 4 of 9 cases predictively showed bcl-6mutations. The frequency of bcl-6 mutations was comparable in both subsets, with mutations being biallelic, and in 3 of 8 cases indicative of clonal origins. Surprisingly, intraclonal variation, which is not a feature of VH genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation of the VH and bcl-6 loci may not necessarily occur in tandem in CLL, suggesting diverse pathways operating on the 2 genes.

scholarly journals Differential Rates of Somatic Hypermutation in VH Genes Among Subsets of Chronic Lymphocytic Leukemia Defined by Chromosomal Abnormalities

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 4153-4160 ◽  
Author(s):  
David G. Oscier ◽  
Andrew Thompsett ◽  
Delin Zhu ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Mutation ◽  
Chromosomal Abnormalities ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Karyotypic Abnormality ◽  
Trisomy 12 ◽  
History Of ◽  
Vh Genes

Abstract Chronic lymphocytic leukemia (CLL) is a B-cell tumor involving small lymphocytes that generally express the CD5 antigen and low levels of surface Ig. Within this definition, there is heterogeneity among cases in cell morphology, karyotypic abnormalities, and clinical course. Trisomy 12, the most frequent karyotypic abnormality, is commonly found in a subset of CLL with atypical morphology. It has also been associated with advanced disease, and possibly with a less favorable prognosis. A further subset of cases with abnormalities involving chromosome 13q14 have typical lymphocyte morphology. Occasionally, the two abnormalities are found together. To assess the clonal history of the cell of origin in disease subsets defined by these two chromosomal abnormalities, we investigated the usage of VH genes and the pattern of somatic mutation in 10 cases of trisomy 12 with atypical morphology and eight cases of 13q14 abnormality with typical morphology. In addition, four cases with both chromosomal abnormalities were analyzed. Results confirm a common usage of the VH1 family in all subsets. However, the patterns of somatic mutation were distinct, with cases of trisomy 12 showing a minimal level of mutation (mean ± SD, 0.34% ± 0.86%) and cases of 13q14 abnormality showing significant levels (6.5% ± 1.67%). The four cases with both abnormalities showed a mixed pattern. All mutated cases had intraclonal homogeneity, and three of 10 had a pattern indicative of antigen selection. These results suggest that the clonal history of the two subsets of CLL may differ.

Somatic mutation of bcl-6 genes can occur in the absence of VH mutations in chronic lymphocytic leukemia

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3534-3540 ◽  
Author(s):  
Surinder S. Sahota ◽  
Zadie Davis ◽  
Terry J. Hamblin ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
V Genes ◽  
History Of ◽  
Vh Genes ◽  
V Region

Abstract Somatic mutation in immunoglobulin variable (V) region genes occurs largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the cell of origin. Recently, it has been found that chronic lymphocytic leukemia (CLL) consists of 2 subsets, each with a different clinical course, one with unmutated VH genes consistent with a naive B cell, and the other with mutated VH genes consistent with transit through the germinal center. However, somatic mutation also occurs at another distinct locus, the 5′ noncoding region of thebcl-6 gene, in both B-cell tumors and in normal germinal center B cells. To probe the suggestive link between the occurrence of mutations in VH and bcl-6 genes, we analyzed the nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated VH genes, with 4 of 10 cases clearly showing mutations inbcl-6. In those CLLs defined by somatically mutated VH genes, 4 of 9 cases predictively showed bcl-6mutations. The frequency of bcl-6 mutations was comparable in both subsets, with mutations being biallelic, and in 3 of 8 cases indicative of clonal origins. Surprisingly, intraclonal variation, which is not a feature of VH genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation of the VH and bcl-6 loci may not necessarily occur in tandem in CLL, suggesting diverse pathways operating on the 2 genes.

scholarly journals De Novo CD5+ Diffuse Large B-Cell Lymphomas Express VH Genes With Somatic Mutation

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1145-1151 ◽  
Author(s):  
Masanori Taniguchi ◽  
Kouji Oka ◽  
Atsunori Hiasa ◽  
Motoko Yamaguchi ◽  
Toshiyuki Ohno ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cellular Origin ◽  
Vh Gene ◽  
Vh Genes ◽  
Large B Cell

Abstract To clarify the cellular origin of de novo CD5+ diffuse large B-cell lymphoma (CD5+ DLBL), particularly in comparison with other CD5+ B-cell neoplasms such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), we analyzed the nucleotide sequence of the Ig heavy chain variable region (IgVH) genes of de novo CD5+ DLBL cases. All 4 cases examined had extensive somatic mutations in contrast with CLL or MCL. The VH gene sequences of de novo CD5+ DLBL displayed 86.9% to 95.2% homology with the corresponding germlines, whereas those of simultaneously analyzed CLL and MCL displayed 97.6% to 100% homology. The VH family used was VH3 in 1 case, VH4 in 2 cases, and VH5 in 1 case. In 2 of 4 examined cases, the distribution of replacement and silent mutations over the complementarity determining region and framework region in the VH genes was compatible with the pattern resulting from the antigen selection. Clinically, CD5+DLBL frequently involved a variety of extranodal sites (12/13) and lymph node (11/13). Immunophenotypically, CD5+ DLBL scarcely expressed CD21 and CD23 (3/13 and 2/13, respectively). These findings indicate that de novo CD5+ DLBL cells are derived from a B-1 subset distinct from those of CLL or MCL.

The Restricted VH-Gene Usage Is of Prognostic Value in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1911-1911 ◽  
Author(s):  
Jan Philippé ◽  
Femke Van Bockstaele ◽  
Kaatje Smits ◽  
Fritz Offner ◽  
Bruno Verhasselt ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Prognostic Value ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Gene Usage ◽  
Vh Gene ◽  
Vh Genes ◽  
Cell Chronic Lymphocytic Leukemia

Abstract In B-cell chronic lymphocytic leukemia (B-CLL) the mutation status of the immunoglobulin variable heavy chain gene (VH) is known as a prognostic factor. We have investigated if specific VH-gene usage is of additional prognostic importance regarding survival. Peripheral blood samples from 147 B-CLL patients were analysed for VH usage. Recombinations occurring in at least 5% of cases were studied in depth. The most frequently used VH-gene segments were VH1-69 (10.9%), VH3-7 (7.5%), VH3-30 (6.8%), VH4-34 (6.8%), VH3-21 (6.1%), VH3-23 (6.1%), and VH3-33 (5.4%). The VH gene usage was compared with mutation status, cytogenetic abnormalities and survival. Comparison with age matched controls reveals the restricted VH gene usage in B-CLL. VH gene usage showed a distinct prognostic value (p=0.01) when the patients using VH genes with bad prognosis were grouped together (VH1-69, VH3-21, VH3-23 and VH3-33; 43% of these patients died) and were compared with the patients using VH genes with a relatively good prognosis (VH3-7, VH3-30 and VH4-34; mortality rate of only 13%). The prognostic significance holds true when all patients were included (p=0.03). Also the mutation status (p=0.04) and cytogenetics (p=0.03) showed a prognostic significance. The VH gene usage did not correlate with mutation status, nor with cytogenetics. On the contrary mutation status and cytogenetics were strongly correlated (p<0.00001). These findings are highly suggestive for VH gene usage to offer additional prognostic information to the other well established prognostic parameters. In conclusion, a bias to the specific VH gene segments involved in B-CLL supports the concept that B-CLL arises from B cells driven by specific antigens/superantigens which is different from a stochastic event in the elderly B-cell population. Moreover, the immunoglobulin specificity reveals specific subgroups with differing prognosis.

scholarly journals VH Gene Analysis of Clonally Related IgM and IgG From Human Lymphoplasmacytoid B-Cell Tumors With Chronic Lymphocytic Leukemia Features and High Serum Monoclonal IgG

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 238-243 ◽  
Author(s):  
Surinder S. Sahota ◽  
Richard Garand ◽  
Regis Bataille ◽  
Alastair J. Smith ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
High Serum ◽  
Lymphocytic Leukemia ◽  
Clonal Origin ◽  
Mutation Pattern ◽  
Vh Gene ◽  
Vh Genes ◽  
Cell Expression ◽  
Human B Cell

An unusual group of human B-cell tumors with cellular features of chronic lymphocytic leukemia or lymphoplasmacytoid leukemia, together with high levels of a monoclonal IgG serum protein, has been investigated. Analysis of tumor-derived VH genes of neoplastic B lymphocytes was used to determine the clonal relationship between the IgM expressed or secreted by the tumor cells and the IgG serum paraprotein. In all five cases, VH gene sequences showed transcripts of IgM and IgG of common clonal origin. Sequences were derived from VH3 (4 of 5) and VH1 (1 of 5) families and were all highly somatically mutated with strong evidence for antigen selection. There was no intraclonal variation detectable in either IgM or IgG sequences. In 3 of 5 cases, in which monoclonal IgM and IgG were found in serum, the VH genes combined to Cμ or Cγ showed identical mutational patterns. However, in 2 of 5 cases, in which IgM was confined to cell expression with only monoclonal IgG in serum, sequences of the VH transcripts of IgM and IgG showed many shared mutations but also numerous differences. In these cases, the level of mutation was similar in IgM and IgG and both appeared to be antigen selected. In summary, the final neoplastic event in this group of tumors has apparently occurred at the point of isotype switch from IgM to IgG, leading to dual isotype synthesis. In the group that secreted both isotypes, the mutation pattern was identical, indicating either synthesis by a single cell, or silencing of mutational activity before switching. In the group that did not secrete IgM, cells of each isotype were distinct and reflected a divergent mutational history.

scholarly journals VH Gene Analysis of Clonally Related IgM and IgG From Human Lymphoplasmacytoid B-Cell Tumors With Chronic Lymphocytic Leukemia Features and High Serum Monoclonal IgG

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 238-243 ◽  
Author(s):  
Surinder S. Sahota ◽  
Richard Garand ◽  
Regis Bataille ◽  
Alastair J. Smith ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
High Serum ◽  
Lymphocytic Leukemia ◽  
Clonal Origin ◽  
Mutation Pattern ◽  
Vh Gene ◽  
Vh Genes ◽  
Cell Expression ◽  
Human B Cell

Abstract An unusual group of human B-cell tumors with cellular features of chronic lymphocytic leukemia or lymphoplasmacytoid leukemia, together with high levels of a monoclonal IgG serum protein, has been investigated. Analysis of tumor-derived VH genes of neoplastic B lymphocytes was used to determine the clonal relationship between the IgM expressed or secreted by the tumor cells and the IgG serum paraprotein. In all five cases, VH gene sequences showed transcripts of IgM and IgG of common clonal origin. Sequences were derived from VH3 (4 of 5) and VH1 (1 of 5) families and were all highly somatically mutated with strong evidence for antigen selection. There was no intraclonal variation detectable in either IgM or IgG sequences. In 3 of 5 cases, in which monoclonal IgM and IgG were found in serum, the VH genes combined to Cμ or Cγ showed identical mutational patterns. However, in 2 of 5 cases, in which IgM was confined to cell expression with only monoclonal IgG in serum, sequences of the VH transcripts of IgM and IgG showed many shared mutations but also numerous differences. In these cases, the level of mutation was similar in IgM and IgG and both appeared to be antigen selected. In summary, the final neoplastic event in this group of tumors has apparently occurred at the point of isotype switch from IgM to IgG, leading to dual isotype synthesis. In the group that secreted both isotypes, the mutation pattern was identical, indicating either synthesis by a single cell, or silencing of mutational activity before switching. In the group that did not secrete IgM, cells of each isotype were distinct and reflected a divergent mutational history.

Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2562-2568 ◽  
Author(s):  
Delin Zhu ◽  
Helen McCarthy ◽  
Christian H. Ottensmeier ◽  
Peter Johnson ◽  
Terry J. Hamblin ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Single Chain ◽  
Single Chain Fv ◽  
Glycosylation Sites ◽  
Vh Genes

Most patients with follicular lymphoma (FL) have somatically mutated V genes with intraclonal variation, consistent with location in the germinal center site. Using our own and published sequences, we have investigated the frequency of potential N-glycosylation sites introduced into functional VH genes as a consequence of somatic mutation. FL cells were compared with normal memory B cells or plasma cells matched for similar levels of mutation. Strikingly, novel sites were detected in 55 of 70 (79%) patients with FL, compared to 7 of 75 (9%) in the normal B-cell population (P &lt; .001). Diffuse large B-cell lymphoma (DLCL) showed an intermediate frequency (13 of 32 [41%] patients). Myeloma and the mutated subset of chronic lymphocytic leukemia showed frequencies similar to those of normal cells in 5 of 64 (8%) patients and 5 of 40 (13%) patients, respectively. In 3 of 3 random patients with FL, immunoglobulin was expressed as recombinant single-chain Fv inPichia pastoris, and glycosylation was demonstrated. These findings indicate that N-glycosylation of the variable region may be common in FL and in a subset of DLCL. Most novel sites are located in the complementarity-determining regions. VH sequences of nonfunctional VH genes contained few sites, arguing for positive selection in FL. One possibility is that the added carbohydrate in the variable region contributes to interaction with elements in the germinal center environment. This common feature of FL may be critical for tumor behavior.

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

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