Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein.

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.

• 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)

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

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)