scholarly journals Immunoglobulin gene rearrangements and expression in diffuse histiocytic lymphomas reveal cellular lineage, molecular defects, and sites of chromosomal translocation

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 391-397 ◽  
Author(s):  
KA Siminovitch ◽  
JP Jensen ◽  
AL Epstein ◽  
SJ Korsmeyer
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Heavy Chain ◽  
Light Chain ◽  
Cell Lineage ◽  
Chromosomal Translocation ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Light Chain Gene

Abstract We have examined the immunoglobulin gene configurations in cell lines from eight patients with diffuse histiocytic lymphoma in order to establish the cellular lineage and stage of differentiation of these lymphomas. The presence of heavy and light chain gene rearrangements as well as heavy chain class switching in seven cells placed these tumors within the B cell lineage. In contrast, one cell (SU-DHL-1), which lacks B cell-restricted surface antigens, retained germline heavy and light chain loci, indicating that it may represent a true histiocyte or uncommitted cell. Truncated RNAs for both the heavy and light chain immunoglobulins were responsible for the lack of surface immunoglobulin in the SU-DHL-2 cell line. Another cell line (SU-DHL-6), which possesses a t(14;18)(q32;q21) translocation, demonstrated an unexpected recombination within its heavy chain gene locus that may be the interchromosomal breakpoint.

scholarly journals Immunoglobulin gene rearrangements and expression in diffuse histiocytic lymphomas reveal cellular lineage, molecular defects, and sites of chromosomal translocation

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 391-397
Author(s):  
KA Siminovitch ◽  
JP Jensen ◽  
AL Epstein ◽  
SJ Korsmeyer
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Heavy Chain ◽  
Light Chain ◽  
Cell Lineage ◽  
Chromosomal Translocation ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Light Chain Gene

We have examined the immunoglobulin gene configurations in cell lines from eight patients with diffuse histiocytic lymphoma in order to establish the cellular lineage and stage of differentiation of these lymphomas. The presence of heavy and light chain gene rearrangements as well as heavy chain class switching in seven cells placed these tumors within the B cell lineage. In contrast, one cell (SU-DHL-1), which lacks B cell-restricted surface antigens, retained germline heavy and light chain loci, indicating that it may represent a true histiocyte or uncommitted cell. Truncated RNAs for both the heavy and light chain immunoglobulins were responsible for the lack of surface immunoglobulin in the SU-DHL-2 cell line. Another cell line (SU-DHL-6), which possesses a t(14;18)(q32;q21) translocation, demonstrated an unexpected recombination within its heavy chain gene locus that may be the interchromosomal breakpoint.

scholarly journals ImmunoglobulinλGene Rearrangement Can PrecedeκGene Rearrangement

1990 ◽  
Vol 1 (1) ◽  
pp. 53-57 ◽  
Author(s):  
Jörg Berg ◽  
Mindy Mcdowell ◽  
Hans-Martin Jäck ◽  
Matthias Wabl
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Light Chain ◽  
Gene Rearrangement ◽  
Germ Line ◽  
Stochastic Theory ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Line Configuration ◽  
Chain Gene Rearrangement

Immunoglobulin genes are generated during differentiation of B lymphocytes by joining gene segments. A mouse pre-B cell contains a functional immunoglobulin heavy-chain gene, but no light-chain gene. Although there is only one heavy-chain locus, there are two lightchain loci:κandλ.It has been reported thatκloci in the germ-line configuration are never (in man) or very rarely (in the mouse) present in cells with functionally rearrangedλ-chain genes. Two explanations have been proposed to explain this: (a) the ordered rearrangement theory, which postulates that light-chain gene rearrangement in the pre-B cell is first attempted at theκlocus, and that only upon failure to produce a functionalκchain is there an attempt to rearrange theλlocus; and (b) the stochastic theory, which postulates that rearrangement at theλlocus proceeds at a rate that is intrinsically much slower than that at theκlocus. We show here thatλ-chain genes are generated whether or not theκlocus has lost its germ-line arrangement, a result that is compatible only with the stochastic theory.

scholarly journals Immunoglobulin gene rearrangements in hairy cell leukemia

Blood ◽  
1984 ◽  
Vol 64 (1) ◽  
pp. 99-104 ◽  
Author(s):  
ML Cleary ◽  
GS Wood ◽  
R Warnke ◽  
J Chao ◽  
J Sklar
Keyword(s):  
Heavy Chain ◽  
Light Chain ◽  
Hairy Cell Leukemia ◽  
Splenic Tissue ◽  
Chain Gene ◽  
Immunoglobulin Gene ◽  
Hairy Cell ◽  
Cell Of Origin ◽  
Cell Leukemia ◽  
Light Chain Gene

Studies of hairy cell leukemia have yielded conflicting data about the cell of origin in this disease. To investigate this issue, we have examined the state of immunoglobulin genes in the cells of 11 randomly selected spleens showing histologic involvement with hairy cell leukemia. DNA was extracted from splenic tissue samples and digested with restriction endonucleases. Following agarose gel electrophoresis and transfer to nitrocellulose filters or activated nylon membranes, splenic DNA was hybridized with radiolabeled DNA fragment probes specific for the constant regions of the immunoglobulin heavy chain and kappa and lambda light chain genes. Autoradiograms of the hybridized DNA in each case revealed rearrangements of a heavy chain gene and at least one light chain gene. In addition, immunophenotyping of cellular immunoglobulin polypeptides was carried out on frozen tissue sections from all but one case. In each case in which an immunoglobulin polypeptide could be detected, a rearrangement was present in the DNA of the corresponding immunoglobulin gene. These studies offer strong evidence for endogenous immunoglobulin synthesis in hairy cells and for the B lymphocytic character of this leukemia.

RAG-1 and RAG-2 are not sufficient to direct all phases of immunoglobulin gene rearrangement in pre-B-cell lines

1993 ◽  
Vol 13 (7) ◽  
pp. 3890-3899
Author(s):  
L C Wang ◽  
N Rosenberg
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Heavy Chain ◽  
Gene Rearrangement ◽  
Chain Gene ◽  
Immunoglobulin Gene ◽  
Heavy Chain Gene ◽  
Rag 1 ◽  
Fusion Experiments

To probe the factors controlling immunoglobulin heavy-chain gene rearrangement, we analyzed Abelson virus-transformed pre-B-cell lines that fail to undergo VH-to-DJH joining at an appreciable frequency. Despite this feature, some of these cell lines (rechi) rearrange an extrachromosomal recombination substrate at levels normal for transformed pre-B cells. Others (reclo) rearrange these substrates at levels characteristic of nonlymphoid hematopoietic cells. The DJH rearrangements from a representative rechi cell line were aberrant, suggesting that these cells probably fail to complete heavy-chain gene assembly because some of the necessary cis-acting signals are missing. In contrast, both DJH rearrangements from a reclo cell line appeared normal in structure, indicating that trans-acting factors necessary for recombination might be missing. Introduction of the RAG-1 and RAG-2 genes, genes encoding two such factors, failed to confer a rechi phenotype to these cells. However, fusion of the reclo cells to a rechi cell line generated a high frequency of rechi hybrids. In addition, most of the hybrids rearranged the endogenous kappa light-chain locus. Neither the rechi phenotype nor kappa-chain rearrangement correlated with levels of RAG-1 and RAG-2 expression in all of the hybrids. Thus, both gene transfer and cell fusion experiments indicate that RAG-1 and RAG-2 are not sufficient to activate immunoglobulin gene recombination in at least some pre-B-cell lines. In addition, the fusion experiments suggest that two gene products in addition to RAG-1 and RAG-2 may be required for kappa-gene rearrangement.

scholarly journals Richter's syndrome with different immunoglobulin light chains and different heavy chain gene rearrangements

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 571-575 ◽  
Author(s):  
JJ van Dongen ◽  
H Hooijkaas ◽  
JJ Michiels ◽  
G Grosveld ◽  
A de Klein ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Light Chain ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
B Cell Differentiation ◽  
Heavy Chain Gene ◽  
Susceptible Host ◽  
Richter’S Syndrome

Abstract In a patient with Richter's syndrome, the chronic lymphocytic leukemia (CLL) expressed lambda, mu, and delta immunoglobulin (lg) chains and the non-Hodgkin lymphoma (NHL) kappa, mu, and delta lg chains. The difference in lg light chain expression suggests that the CLL and NHL are independent malignancies, or that the oncogenic event occurred in a B cell differentiation stage after the heavy chain gene rearrangements but before the selection of the light chain. Analysis of DNA by Southern blotting revealed that the lg heavy chain genes of the two malignancies were rearranged in a different way. We therefore conclude that in this patient the NHL cannot be regarded as a progression of the CLL but should most likely be considered as an independent B cell malignancy, which arose in a susceptible host.

scholarly journals Richter's syndrome with different immunoglobulin light chains and different heavy chain gene rearrangements

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 571-575 ◽  
Author(s):  
JJ van Dongen ◽  
H Hooijkaas ◽  
JJ Michiels ◽  
G Grosveld ◽  
A de Klein ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Light Chain ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
B Cell Differentiation ◽  
Heavy Chain Gene ◽  
Susceptible Host ◽  
Richter’S Syndrome

In a patient with Richter's syndrome, the chronic lymphocytic leukemia (CLL) expressed lambda, mu, and delta immunoglobulin (lg) chains and the non-Hodgkin lymphoma (NHL) kappa, mu, and delta lg chains. The difference in lg light chain expression suggests that the CLL and NHL are independent malignancies, or that the oncogenic event occurred in a B cell differentiation stage after the heavy chain gene rearrangements but before the selection of the light chain. Analysis of DNA by Southern blotting revealed that the lg heavy chain genes of the two malignancies were rearranged in a different way. We therefore conclude that in this patient the NHL cannot be regarded as a progression of the CLL but should most likely be considered as an independent B cell malignancy, which arose in a susceptible host.

scholarly journals Immunoglobulin gene rearrangements in hairy cell leukemia

Blood ◽  
1984 ◽  
Vol 64 (1) ◽  
pp. 99-104 ◽  
Author(s):  
ML Cleary ◽  
GS Wood ◽  
R Warnke ◽  
J Chao ◽  
J Sklar
Keyword(s):  
Heavy Chain ◽  
Light Chain ◽  
Hairy Cell Leukemia ◽  
Splenic Tissue ◽  
Chain Gene ◽  
Immunoglobulin Gene ◽  
Hairy Cell ◽  
Cell Of Origin ◽  
Cell Leukemia ◽  
Light Chain Gene

Abstract Studies of hairy cell leukemia have yielded conflicting data about the cell of origin in this disease. To investigate this issue, we have examined the state of immunoglobulin genes in the cells of 11 randomly selected spleens showing histologic involvement with hairy cell leukemia. DNA was extracted from splenic tissue samples and digested with restriction endonucleases. Following agarose gel electrophoresis and transfer to nitrocellulose filters or activated nylon membranes, splenic DNA was hybridized with radiolabeled DNA fragment probes specific for the constant regions of the immunoglobulin heavy chain and kappa and lambda light chain genes. Autoradiograms of the hybridized DNA in each case revealed rearrangements of a heavy chain gene and at least one light chain gene. In addition, immunophenotyping of cellular immunoglobulin polypeptides was carried out on frozen tissue sections from all but one case. In each case in which an immunoglobulin polypeptide could be detected, a rearrangement was present in the DNA of the corresponding immunoglobulin gene. These studies offer strong evidence for endogenous immunoglobulin synthesis in hairy cells and for the B lymphocytic character of this leukemia.

scholarly journals Rearrangement and Expression of Immunoglobulin Light Chain Genes Can Precede Heavy Chain Expression during Normal B Cell Development in Mice

1999 ◽  
Vol 189 (1) ◽  
pp. 75-88 ◽  
Author(s):  
Tatiana I. Novobrantseva ◽  
Verena M. Martin ◽  
Roberta Pelanda ◽  
Werner Müller ◽  
Klaus Rajewsky ◽  
...  
Keyword(s):  
B Cell ◽  
Light Chain ◽  
Single Cell Analysis ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Cell Analysis ◽  
Wild Type ◽  
Immunoglobulin Light Chain ◽  
Light Chain Gene ◽  
Mouse Mutants

In mouse mutants incapable of expressing μ chains, VκJκ joints are detected in the CD43+ B cell progenitors. In agreement with these earlier results, we show by a molecular single cell analysis that 4–7% of CD43+ B cell progenitors in wild-type mice rearrange immunoglobulin (Ig)κ genes before the assembly of a productive VHDHJH joint. Thus, μ chain expression is not a prerequisite to Igκ light chain gene rearrangements in normal development. Overall, ∼15% of the total CD43+ B cell progenitor population carry Igκ gene rearrangements in wild-type mice. Together with the results obtained in the mouse mutants, these data fit a model in which CD43+ progenitors rearrange IgH and Igκ loci independently, with a seven times higher frequency in the former. In addition, we show that in B cell progenitors VκJκ joining rapidly initiates κ chain expression, irrespective of the presence of a μ chain.

scholarly journals Normal human B cells display ordered light chain gene rearrangements and deletions.

1982 ◽  
Vol 156 (4) ◽  
pp. 975-985 ◽  
Author(s):  
S J Korsmeyer ◽  
P A Hieter ◽  
S O Sharrow ◽  
C K Goldman ◽  
P Leder ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Light Chain ◽  
Developmental Process ◽  
Germ Line ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Lambda Light Chain ◽  
Light Chain Gene

Human kappa-producing B cell lines and leukemias retain their excluded lambda light chain genes in the germ line configuration, whereas transformed lambda-producing B cells uniformly rearrange or delete their kappa genes (12). Whether the unexpected lambda gene recombinations within malignant lambda-producing B cells reflect a normal developmental process or are secondary to transformation and specific chromosomal translocations was uncertain. To resolve this issue, we purified circulating lambda-bearing B cells from a normal individual to 97% purity by using a series of negative selection steps and a final positive selection on a cell sorter. Over 95% of the collective kappa genes in these lambda B cells were no longer in their germ line form, with the majority (60%) deleted and the remainder present but in a rearranged state. The chromosomal loss of the germ line kappa genes included the joining (J kappa) segments as well as the constant (C kappa) region, yet the particular variable (V kappa) gene family studied was spared. In addition, the incidence of kappa gene deletions was higher in long-term than in freshly transformed lambda B cell lines. This implies that the deletion of aberrantly rearranged kappa genes may occur as a second event. Such a mechanism would serve to eliminate aberrant transcripts and light chain fragments that might interfere with the synthesis and assembly of effective immunoglobulin molecules. Thus, despite the nearly equal usage of kappa and lambda light chain genes in man, there appears to be a sequential order to their expression during normal B cell ontogeny in which kappa gene rearrangements precede those of lambda.

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