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.

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.

Analysis of VH gene expression in CD5+ and CD5- B-cell chronic lymphocytic leukemia

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3883-3890 ◽  
Author(s):  
K Maloum ◽  
F Davi ◽  
C Magnac ◽  
O Pritsch ◽  
E McIntyre ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Random Distribution ◽  
Lymphocytic Leukemia ◽  
Mutation Pattern ◽  
Vh Gene ◽  
Vh Genes ◽  
Multiple Myelomas ◽  
Differentiation Stage ◽  
Follicular Lymphomas

In contrast to highly mutated follicular lymphomas and multiple myelomas, chronic lymphocytic leukemias (CLLs) frequently express VH genes in germline configuration. It is currently unclear whether this difference is related to the expression of CD5 or to the differentiation stage of the B cell when malignant transformation occurs. We have studied the VH sequence of 11 cases of CD5- B-CLL to address the question whether CD5- B-CLL are derived from naive pregerminal B cells (low mutation pattern) or from germinal center- derived memory B cells (high mutation pattern). Among the 12 detected rearrangements (2 distinct rearrangements in 1 case) VH1 family was found in 2, VH2 in 2, VH3 in 4, and VH4 in 4. Nine different VH genes were detected among the 12 rearrangements, including 2 cases expressing V1–69 (51p1) and 1 case expressing V4–39 (VH4.18), previously reported to be overexpressed in CD5+ B-CLL. A higher mutation pattern, following a random distribution, was observed when compared with classical CD5+ B- CLL. However, as reported in normal B cells, these results appeared to be related to membrane Ig phenotype (less mutations in membrane mu delta-expressing forms in leukemias expressing exclusively membrane mu). Overall, the differences found when comparing the mutational profile with classical CD5+ B-CLL were not clearcut and might be explained more by the membrane isotype (mu v mu delta) than by CD5 expression.

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.

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.

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.

Immunoglobulin VH gene expression in human B cell lines and tumors: biased VH gene expression in chronic lymphocytic leukemia

1989 ◽  
Vol 1 (4) ◽  
pp. 362-366 ◽  
Author(s):  
Ton Logtenberg ◽  
Mieke E. M. Schutte ◽  
Giorgio Inghirami ◽  
Jeffrey E. Berman ◽  
Frits H. J. Gmelig-Meyling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Lymphocytic Leukemia ◽  
Vh Gene ◽  
Human B Cell

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.

scholarly journals Variable region gene analysis of an isotype-switched (IgA) variant of chronic lymphocytic leukemia

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2287-2297 ◽  
Author(s):  
DF Friedman ◽  
JS Moore ◽  
J Erikson ◽  
J Manz ◽  
J Goldman ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Early Stage ◽  
Lymphocytic Leukemia ◽  
Gene Analysis ◽  
Pokeweed Mitogen ◽  
B Cell Differentiation ◽  
Germline Gene ◽  
Vh Gene

Abstract Chronic lymphocytic leukemia of B-cell origin (B-CLL) is generally thought to arise by neoplastic transformation of B lymphocytes, which express CD5 and have features of an early stage of B-cell differentiation. To study isotype-switched B-CLL as a potentially more differentiated variant, we performed genetic and functional immunoglobulin (Ig) gene analysis in two cases of CD5+ B-CLL in which the peripheral blood mononuclear cells (PBMC) secreted predominantly IgA (CLL-249) or IgG (CLL-412) when stimulated with pokeweed mitogen in vitro. By cDNA sequencing and by studies of CLL-heterohybridomas, CLL- 249 expresses the heavy chain constant region C alpha as anticipated, while CLL-412 expresses C mu, not C gamma. In CLL-249, the expressed VH gene is 98% homologous to VH26, a germline VH3 gene that occurs frequently in the fetal repertoire, and which has been associated with anti-DNA specificity. The VL gene of CLL-249 is a lambda VL gene for which the germline sequence is not known. In CLL-412, the VH gene is 100% homologous to the VH1 gene of a published anti-DNA antibody (21/28), and is probably a germline gene sequence; the VL gene is 100% homologous to 15AVKI, also a germline gene. The supernatant antibody of the CLL-412 heterohybridoma is an IgM-kappa, which reacts with ssDNA and cardiolipin. The CLL-249 heterohybridoma secreted IgA-lambda, which bound none of the antigens tested, a finding that may be related to amino acid differences from the probable germline V genes. The demonstration of an in vivo isotype-switched variant, such as CLL-249, suggests that B-CLL may be a heterogeneous group of clonal disorders, of which less common variants may have features of more differentiated B-cell stages, such as isotype switching.

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