Abstract | BACKGROUND:
Heavy-chain diseases (HCDs) are human lymphoproliferative neoplasias that are characterized by the secretion of truncated immunoglobulin heavy chains devoid of light chains. We have previously proposed--by analogy to the process by which mutated growth factor receptors can be oncogenic--that because the genetic defects in HCDs result in the production of abnormal membrane-associated heavy chains lacking an antigen-binding domain, these abnormal B-cell antigen receptors might engage in ligand-independent signalling. Normal pre-B-cell development requires the presence of the pre-B-cell receptor, formed by the association of mu heavy chains with two polypeptides--so-called surrogate light chains, Vpre-B and lambda 5--that are homologous to the variable and constant portions of immunoglobulin light chains, respectively. To assess whether amino-terminal truncation of membrane-associated heavy chains results in their constitutive activation, we have examined the ability of a HCD-associated mu protein to promote pre-B-cell development in transgenic mice. RESULTS: When the mu HCD transgene is introduced into SCID mice, CD43- pre-B cells develop normally. To determine whether this pre-B-cell development requires surrogate light chains, we backcrossed mice expressing full-length or truncated mu transgenes with lambda 5-deficient mice. Our results show that the truncated heavy chain, but not the normal chain, is able to promote pre-B-cell development in the absence of lambda 5. We also show that truncated mu chains spontaneously aggregate at the surface of bone marrow cells. CONCLUSIONS: Expression of the truncated mu heavy chain overrides a tightly controlled step of pre-B-cell development, which strongly suggests that a constitutive signal is delivered by the truncated mu chain disease protein. The self-aggregation of mu chain disease proteins might account for this constitutive activation. We conclude that amino-terminal truncation of heavy chains could play a role in the genesis of HCD neoplasia if it occurs at an appropriate stage of B-cell differentiation, namely in a mature B cell.
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Authors | D Corcos, O Dunda, C Butor, J Y Cesbron, P Lorès, D Bucchini, J Jami |
Journal | Current biology : CB
(Curr Biol)
Vol. 5
Issue 10
Pg. 1140-8
(Oct 01 1995)
ISSN: 0960-9822 [Print] England |
PMID | 8548286
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antigens, CD
- DNA Primers
- Immunoglobulin Light Chains
- Immunoglobulin Light Chains, Surrogate
- Immunoglobulin gamma-Chains
- Immunoglobulin mu-Chains
- Leukosialin
- Membrane Glycoproteins
- Peptide Fragments
- Sialoglycoproteins
- Spn protein, mouse
- heavy chain disease proteins, human
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Topics |
- Animals
- Antigens, CD
- B-Lymphocytes
(cytology, immunology)
- Base Sequence
- Cell Differentiation
- DNA Primers
- Gene Deletion
- Heavy Chain Disease
- Hematopoietic Stem Cells
(cytology)
- Immunoglobulin Light Chains
(genetics, metabolism)
- Immunoglobulin Light Chains, Surrogate
- Immunoglobulin gamma-Chains
(metabolism)
- Immunoglobulin mu-Chains
(genetics, metabolism)
- Leukosialin
- Membrane Glycoproteins
(genetics, metabolism)
- Mice
- Mice, Inbred BALB C
- Mice, Transgenic
- Molecular Sequence Data
- Peptide Fragments
(metabolism)
- Sialoglycoproteins
(metabolism)
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