Immunoglobulin gene alterations in human heavy chain diseases

Heavy chain diseases (HCDs) are B-cell proliferative disorders characterized by the production of monoclonal, incomplete, immunoglobulin (Ig) heavy chains (HCs) without associated light chains (LCs). These abnormal HCs are produced as a consequence of HC gene alterations in the neoplastic B cells. HC gene alterations will also impact on surface HC, which is part of the B-cell receptor (BCR), a crucial player in lymphocyte activation by antigen. The selective advantage conferred to mutant cells by abnormal BCR without an antigen-binding domain may be explained by activation of ligand-independent signaling, in analogy to what has been shown for mutated oncogenic growth factor receptors. Here we review data obtained from mouse models showing abnormal, constitutive activity of HCD-BCR, and we discuss the possible mechanism involved, namely, aberrant spontaneous self-aggregation. This self-aggregation might occur as a consequence of escape from the chaperone immunoglobulin binding protein (BiP) and from the anti-aggregation effect of LC association. The concept of misfolding-induced signaling elaborated here may extend to other pathologies termed conformational diseases.

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High-frequency homologous recombination between duplicate chromosomal immunoglobulin mu heavy-chain constant regions

Molecular and Cellular Biology ◽

10.1128/mcb.9.12.5500-5507.1989 ◽

1989 ◽

Vol 9 (12) ◽

pp. 5500-5507

Author(s):

M D Baker

Keyword(s):

Homologous Recombination ◽

Heavy Chain ◽

High Frequency ◽

Gene Replacement ◽

Immunoglobulin M ◽

Hybridoma Cells ◽

Immunoglobulin Gene ◽

Reciprocal Recombination ◽

Base Pair Deletion ◽

Frequent Event

Homologous recombination was used in a previous study to correct a 2-base-pair deletion in the third constant domain (Cmu3) of the haploid chromosomal mu gene in a mutant hybridoma cell line by transfer of a pSV2neo vector bearing a subfragment of the normal Cmu region (M.D. Baker, N. Pennell, L. Bosnoyan, and M.J. Shulman, Proc. Natl. Acad. Sci. USA 85:6432-6436, 1988). In these experiments, both gene replacement and single reciprocal crossover events were found to restore normal, cytolytic 2,4,6-trinitrophenyl-specific immunoglobulin M production to the mutant cells. In the cases of single reciprocal recombination, the structure of the recombinant mu gene is such that the normal Cmu region, in its correct position 3' of the expressed 2,4,6-trinitrophenyl-specific heavy-chain variable region, is separated from the mutant Cmu region by the integrated vector sequences. I report here that homologous recombination occurs with high frequency between the duplicate Cmu regions in mitotically growing hybridoma cells. The homologous recombination events were easily detected since they generated hybridomas that were phenotypically different from the parental cells. Analysis of the recombinant cells suggests that gene conversion is the most frequent event, occurring between 60 and 73% of the time. The remaining events consisted of single reciprocal crossovers. Intrachromatid double reciprocal recombination was not detected. The high frequency of recombination, the ability to isolate and analyze the participants in the recombination reactions, and the capacity to generate specific modifications in the immunoglobulin Cmu regions by gene targeting suggest that this system will be useful for studying mammalian chromosomal homologous recombination. Moreover, the ability to specifically modify the chromosomal immunoglobulin genes by homologous recombination should facilitate studies of immunoglobulin gene regulation and expression and provide a more convenient of engineering specifically modified antibody.

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Heavy-chain diseases

Multiple Myeloma and Related Disorders ◽

10.1201/b13347-35 ◽

2004 ◽

pp. 420-428

Author(s):

Jean-Paul Fermand ◽

Jean-Claude Brouet

Keyword(s):

Heavy Chain ◽

Heavy Chain Diseases

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Immunoglobulin gene rearrangements in normal mouse B cells

Molecular and Cellular Biology ◽

10.1128/mcb.2.7.829-836.1982 ◽

1982 ◽

Vol 2 (7) ◽

pp. 829-836

Author(s):

P Early ◽

C Nottenburg ◽

I Weissman ◽

L Hood

Keyword(s):

B Cells ◽

Heavy Chain ◽

Germ Line ◽

Gene Segment ◽

Immunoglobulin M ◽

Chain Gene ◽

Allelic Exclusion ◽

Immunoglobulin Gene ◽

Spleen Cells ◽

Surface Immunoglobulin

We have analyzed the structure of rearranged mu heavy-chain genes obtained from the genomic DNA of normal BALB/c mouse spleen cells expressing surface immunoglobulin M. Examples were found of two types of nonproductive rearrangements, which may be responsible for allelic exclusion in normal B cells. In one of these rearrangements, a germ line D gene segment has joined to the JH4 gene segment but no V/D joining has occurred. We present evidence that D gene segments lie as a cluster between V and J gene segments in the germ line. A comparison of conserved sequences in V and D gene segments suggests that the D gene segments, which are found only in the heavy-chain gene family, may have evolved from V gene segments similar to the Vk family.

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Heavy Chain Diseases

Encyclopedia of Immunology ◽

10.1006/rwei.1999.0274 ◽

1998 ◽

pp. 1053-1056

Author(s):

Jean-Louis Preud'homme

Keyword(s):

Heavy Chain ◽

Heavy Chain Diseases

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Some Protein Disorders Associated with Neoplasms of Plasma Cells and Lymphocytes: Heavy Chain Diseases**Supported by U. S. Public Health Service Grants #AMO 2594, #AMO 1431, and #AMO 5094 and the Health Research Council of the City of New York.

Progress in Immunology ◽

10.1016/b978-0-12-057550-3.50061-2 ◽

1971 ◽

pp. 745-760 ◽

Cited By ~ 3

Author(s):

EDWARD C. FRANKLIN

Keyword(s):

Public Health ◽

New York ◽

Health Service ◽

Heavy Chain ◽

Health Research ◽

Research Council ◽

Plasma Cells ◽

Heavy Chain Diseases ◽

Health Research Council ◽

The City

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Clinical and laboratory characteristics of acute leukemia with the 4;11 translocation

Blood ◽

10.1182/blood.v67.3.689.689 ◽

1986 ◽

Vol 67 (3) ◽

pp. 689-697 ◽

Cited By ~ 87

Author(s):

J Mirro ◽

G Kitchingman ◽

D Williams ◽

GJ Lauzon ◽

CC Lin ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

B Cell ◽

Heavy Chain ◽

Gene Rearrangement ◽

Lymphoblastic Leukemia ◽

Flow Cytometric Analysis ◽

Terminal Deoxynucleotidyl Transferase ◽

Immunoglobulin Gene ◽

Immunoglobulin Gene Rearrangement

Abstract This report describes the clinical and laboratory features of seven cases of acute leukemia associated with the 4;11 chromosomal translocation. All seven children had acute lymphoblastic leukemia by standard morphologic and cytochemical criteria. Leukemic blasts from six of seven patients were terminal deoxynucleotidyl transferase- positive. Immunologic phenotyping suggested the leukemias were of B cell origin; blasts from five patients expressed HLA-DR and p24 (CD-9 antibody), blasts from three patients expressed B4 (CD-19), and blasts from two patients expressed the common acute lymphoblastic leukemia antigen (CD-10). One patient's leukemic blasts contained cytoplasmic immunoglobulin. Analysis of DNA from four of five patients demonstrated additional evidence of B cell differentiation with heavy-chain immunoglobulin gene rearrangement. When DNA from the four patients with heavy-chain immunoglobulin gene rearrangement was analyzed, one patient's DNA demonstrated light-chain immunoglobulin gene rearrangement. However, flow cytometric analysis of blasts from three patients showed the simultaneous expression of the lymphoid-associated antigen B4 (CD-19) and the myeloid-associated antigen My-1 (X-Hapten). Electron microscopic examination of blasts from one patient that expressed both lymphoid- and myeloid-associated antigens demonstrated ultrastructural characteristics of both lineages. These findings suggest that acute leukemia with the t(4;11) abnormality has mixed lineage characteristics as a result of leukemogenesis in a multipotential progenitor cell or aberrant gene expression later in differentiation. Furthermore, serial analysis of karyotype, immunophenotype, and heavy-chain immunoglobulin genes revealed changes in these biologic markers over time, suggesting continued chromosome rearrangement and gene modulation after the leukemogenic event in cells with the t(4;11).

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Tumor detection through the use of immunoglobulin gene rearrangements combined with tissue in situ hybridization

Blood ◽

10.1182/blood.v74.5.1791.1791 ◽

1989 ◽

Vol 74 (5) ◽

pp. 1791-1795 ◽

Cited By ~ 7

Author(s):

NL Seibel ◽

IR Kirsch

Keyword(s):

In Situ Hybridization ◽

T Cell Receptor ◽

Direct Sequencing ◽

Cell Receptor ◽

Specific Gene ◽

Immunoglobulin Gene ◽

Structural Alterations ◽

Leukemias And Lymphomas ◽

Gene Alterations

Abstract Leukemias and lymphomas can now be classified according to the particular immunoglobulin, T-cell receptor, or growth-affecting genes they are expressing. Recognition of the structural alterations of lymphoid DNA has been used to identify neoplasms of previously uncertain lineage, to aid in diagnosis, and to define the state of differentiation of the neoplasm. We have developed a procedurally simple, rapid turnaround technique for using tumor-specific gene alterations as tumor-specific markers. Probes can be constructed that will recognize only the gene expressed in the tumor and not those in any of the normal cells when used with tissue in situ hybridization. We demonstrate the application of direct sequencing of a specific gene of interest from total RNA from a patient with multiple myeloma. A probe is then generated from this sequence and applied directly to patient material.

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