scholarly journals Ig VH gene expression among human follicular lymphomas

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1561-1568 ◽  
Author(s):  
DW Bahler ◽  
MJ Campbell ◽  
S Hart ◽  
RA Miller ◽  
S Levy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Variable Region ◽  
Gene Families ◽  
Peripheral Blood Lymphocytes ◽  
Low Grade ◽  
Normal Peripheral Blood ◽  
Germline Genes ◽  
Vh Gene ◽  
Vh Genes ◽  
Follicular Lymphomas

Abstract Thirty-six randomly selected cases of low grade follicular lymphoma (FL) were analyzed for Ig heavy chain variable region (VH) gene expression. Assignment to one of the six human VH gene families (VH1 to VH6) was made with a polymerase chain reaction-based technique using family-specific leader primers. The frequency of VH family use in FL was found to be similar to that reported for normal peripheral blood lymphocytes and is therefore also roughly proportional to VH family size. To evaluate expression within an individual family, all of the lymphoma VH genes from the middle size VH4 family were sequenced and compared with previously published sequences. Of these eight lymphoma VH sequences, six were most closely related to just two of the 10 known functional VH4 germline genes. Nonrandom usage by FL of the JH3, JH4, and JH5 joining segments was also observed. Nucleotide sequences were also determined for 10 randomly selected lymphoma VH genes from the large VH3 family. With one possible exception, none of these lymphoma VH sequences appear to represent any of the VH3 genes that may be preferentially used in the fetal repertoire.

scholarly journals Ig VH gene expression among human follicular lymphomas

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1561-1568 ◽  
Author(s):  
DW Bahler ◽  
MJ Campbell ◽  
S Hart ◽  
RA Miller ◽  
S Levy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Variable Region ◽  
Gene Families ◽  
Peripheral Blood Lymphocytes ◽  
Low Grade ◽  
Normal Peripheral Blood ◽  
Germline Genes ◽  
Vh Gene ◽  
Vh Genes ◽  
Follicular Lymphomas

Thirty-six randomly selected cases of low grade follicular lymphoma (FL) were analyzed for Ig heavy chain variable region (VH) gene expression. Assignment to one of the six human VH gene families (VH1 to VH6) was made with a polymerase chain reaction-based technique using family-specific leader primers. The frequency of VH family use in FL was found to be similar to that reported for normal peripheral blood lymphocytes and is therefore also roughly proportional to VH family size. To evaluate expression within an individual family, all of the lymphoma VH genes from the middle size VH4 family were sequenced and compared with previously published sequences. Of these eight lymphoma VH sequences, six were most closely related to just two of the 10 known functional VH4 germline genes. Nonrandom usage by FL of the JH3, JH4, and JH5 joining segments was also observed. Nucleotide sequences were also determined for 10 randomly selected lymphoma VH genes from the large VH3 family. With one possible exception, none of these lymphoma VH sequences appear to represent any of the VH3 genes that may be preferentially used in the fetal repertoire.

scholarly journals Localized- and advanced-stage follicular lymphomas differ in their gene expression profiles

Blood ◽  
2020 ◽  
Vol 135 (3) ◽  
pp. 181-190 ◽  
Author(s):  
Annette M. Staiger ◽  
Eva Hoster ◽  
Vindi Jurinovic ◽  
Stefan Winter ◽  
Ellen Leich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Background ◽  
Cox Regression ◽  
Expression Profiles ◽  
Low Grade ◽  
Advanced Stage ◽  
Free Survival ◽  
Molecular Features ◽  
Clinical Stages ◽  
Follicular Lymphomas

Abstract The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an “advanced-stage signature” in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio [HR], 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a “localized-stage signature” had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.

scholarly journals Biased expression of JH-proximal VH genes occurs in the newly generated repertoire of neonatal and adult mice.

1990 ◽  
Vol 171 (3) ◽  
pp. 843-859 ◽  
Author(s):  
B A Malynn ◽  
G D Yancopoulos ◽  
J E Barth ◽  
C A Bona ◽  
F W Alt
Keyword(s):  
Gene Families ◽  
Relative Expression ◽  
Immunodeficient Mice ◽  
Regulatory Interactions ◽  
Adult Mice ◽  
Neonatal Liver ◽  
Vh Gene ◽  
Vh Genes ◽  
Adult Bone ◽  
Insight Into

We have previously demonstrated a dramatic preference for utilization of the most JH-proximal VH gene segments in the newborn liver versus adult spleen. We now examine in detail the relative expression of different VH gene families throughout ontogeny and in immunodeficient mice to gain insight into factors that cause the shift in VH usage. We find that the relative expression of VH gene families remains constant and biased throughout fetal and neonatal liver development. In addition, the primary VH repertoire expressed in neonatal spleen displays a similarly biased, position-dependent VH repertoire. The pattern of VH gene expression begins to change at 5-7 d postnatally and reaches the adult randomized pattern at approximately 2 wk of age. We also find biased expression of JH-proximal VH gene families in adult bone marrow and in spleens of adult leaky scid mice, suggesting that the spontaneously generated repertoire of adult mice is similar to that observed in neonates. Together, these data suggest that a position-dependent repertoire is generated in differentiating pre-B cells at all stages of ontogeny, at least in part, as a result of preferential rearrangement of proximal VH gene segments. Therefore, mechanisms subsequent to V gene rearrangement, such as regulatory interactions and antigen selection, must play a major role in normalizing the repertoire.

scholarly journals VH gene usage is multiple myeloma: complete absence of the VH4.21 (VH4- 34) gene

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2846-2852 ◽  
Author(s):  
MB Rettig ◽  
RA Vescio ◽  
J Cao ◽  
CH Wu ◽  
JC Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Variable Region ◽  
Clonal Deletion ◽  
Gene Usage ◽  
Vh Gene ◽  
Polymerase Chain ◽  
Vh Genes ◽  
Functional Germline ◽  
Autoimmune Phenomena

The immunoglobin heavy chain variable region (VH) gene usage in multiple myeloma (MM) has not been reported, although a few studies have incidentally identified the VH gene rearranged in small cohorts of MM patients. We used a reverse transcriptase-polymerase chain reaction based technique to analyze the VH gene usage in MM. The VH sequences were obtained after amplification of bone marrow cDNA using the seven VH family-specific and constant region primers. The VH sequences of 72 patients were successfully identified. The frequency of VH family usage in decreasing order was VH3>VH4>VH1y>VH5>VH2>VH6>VH7 and corresponded to the functional germline complexity of the VH families. Individual VH genes (VH1–69, VH3–9, VH3–23, and VH3–30) were overrepresented in our cohort of MM patients; some VH genes [VH3–49, VH3–53, and VH4.21 (VH4- 34)], which are rearranged with increased frequency in normal circulating B cells, autoimmune diseases, and other B-cell malignancies, were not detected in any MM patient. Compared with germline sequences, an average of 8.8% (range, 2.7% to 16.5%) of the nucleotides had evidence of mutation within each VH sequence. Based on these results, we conclude that (1) the VH gene usage in MM is unique compared with other malignant and nonmalignant B-cell populations, (2) the physiologic process of clonal deletion functions to remove clones that have rearranged VH genes (VH4.21) capable of expressing antibodies, which recognize self-antigens, and (3) the complete lack of VH4.21 gene rearrangement may help to partially explain the paucity of autoimmune phenomena in MM.

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.

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.

scholarly journals bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1820-1828 ◽  
Author(s):  
M Hanada ◽  
D Delia ◽  
A Aiello ◽  
E Stadtmauer ◽  
JC Reed
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Methylation Status ◽  
Peripheral Blood Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Gene Rearrangements ◽  
Normal Peripheral Blood ◽  
Cell Chronic Lymphocytic Leukemia

Abstract The bcl-2 gene becomes transcriptionally deregulated in the majority of low-grade non-Hodgkin lymphomas as a result of t(14;18) translocations that place the bcl-2 gene at 18q21 into juxtaposition with the Ig heavy- chain locus at 14q32. This chromosomal translocation or similar bcl-2 gene rearrangements involving the Ig light-chain genes have been reported to occur in some cases of B-cell chronic lymphocytic leukemia (B-CLL). We analyzed the structure, methylation, and expression of the bcl-2 gene in 20 cases of B-CLL or closely related variants of this lymphoproliferative disorder, including at least 16 typical examples of CD5+ B-CLL. None of the 20 specimens had evidence of bcl-2 gene rearrangements, based on Southern blot analysis using three different bcl-2 probes. However, immunoblot analysis using antibodies specific for the Bcl-2 protein showed that 14 of 20 cases (70%) contained levels of p26-Bcl-2 that were equal to or greater than those found in a t(14;18)-bearing lymphoma cell line. Furthermore, in 19 of 20 cases (95%), the Bcl-2 protein was present at levels that were 1.7- to 25- fold higher than in normal peripheral blood lymphocytes. These differences in the relative levels of Bcl-2 protein among cases of B- CLL appeared to be functionally significant, in that a preliminary analysis of 3 representative cases showed that CLL cells with higher levels of Bcl-2 protein survived longer in culture and were delayed in their onset of DNA degradation relative to CLL cells with lower Bcl-2 protein levels. Evaluation of the methylation status of the bcl-2 gene using the isoschizomers Msp I and Hpa II, and a probe corresponding to the first major exon of the gene showed complete demethylation of both copies of the bcl-2 gene in a region corresponding to a 2.4-kb Msp I fragment in all 20 cases of B-CLL. In contrast, analysis of 6 of 6 B- cell lines that harbor a t(14;18) was consistent with hypomethylation of only one of the two bcl-2 alleles. Neither copy of the bcl-2 gene was demethylated in this region in 5 of 5 lymphoid cell lines that lack this translocation. However, hypomethylation of the bcl-2 gene did not necessarily correlate with the relative levels of Bcl-2 protein present in the B-CLL cells, suggesting that additional mechanisms for regulating bcl-2 expression are involved.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Murine V kappa gene expression does not follow the VH paradigm.

1989 ◽  
Vol 169 (5) ◽  
pp. 1859-1864 ◽  
Author(s):  
A Kaushik ◽  
D H Schulze ◽  
C Bona ◽  
G Kelsoe
Keyword(s):  
Gene Expression ◽  
Gene Family ◽  
B Lymphocytes ◽  
Gene Rearrangement ◽  
Gene Families ◽  
Genomic Complexity ◽  
Positional Bias ◽  
Vh Gene

V kappa gene family expression among LPS-reactive murine B lymphocytes, unlike that of VH gene families, is not proportional to genomic complexity, i.e., nonstoichiometric. Furthermore, no positional bias for the overexpression of J-proximal V kappa genes (V kappa 21) is observed among neonatal B lymphocytes. Yet, the V kappa 1 and V kappa 9 families located in the center of V kappa locus are preferentially used by neonatal B splenocytes. Thus, the mechanisms of V kappa gene rearrangement and expression appear to differ significantly from those controlling the VH locus.

scholarly journals Preferential use of the VH4 Ig gene family by diffuse large-cell lymphoma

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3072-3082 ◽  
Author(s):  
FJ Hsu ◽  
R Levy
Keyword(s):  
Gene Family ◽  
Cell Lymphoma ◽  
Variable Region ◽  
Gene Families ◽  
Large Cell ◽  
Germline Gene ◽  
Diffuse Large Cell Lymphoma ◽  
Vh Genes ◽  
Large Cell Lymphoma ◽  
Almost All

Abstract Ig heavy chain variable region (VH) genes expressed by human diffuse large-cell lymphoma (DLC) and follicular lymphoma (FL) were identified and analyzed with respect to germline gene families. In 67 cases of FL, VH region genes were expressed in a pattern similar to that of normal B cells, with a predominance of the large VH3 gene family being used. In contrast, of the 17 cases of DLC, there was an extremely biased use of VH genes. Of these DLC tumors, 88% expressed genes from the small VH4 gene family; and even among these tumors, there was a limited use of genes, with 11 cases producing Igs derived from the VH4.21 germline gene. Although most of the VH genes expressed by DLC tumor cells contained mutations with respect to their germline counterparts, almost all of these mutations occurred before the clonal expansion of the tumor. This contrasts with our previous findings of ongoing mutations in FL and represents a fundamental difference between these two malignancies. This preferential gene use implies an important role for the VH4 gene family, and specifically for VH4.21, in the genesis of DLC.

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