PRE-B-CELL DEVELOPMENT IN THE ABSENCE OF LAMBDA-5 IN TRANSGENIC MICE EXPRESSING A HEAVY-CHAIN DISEASE PROTEIN
PRE-B-CELL DEVELOPMENT IN THE ABSENCE OF LAMBDA-5 IN TRANSGENIC MICE EXPRESSING A HEAVY-CHAIN DISEASE PROTEIN
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DOI：
10.1016/s0960-9822(95)00230-2
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发表时间：
1995-10-01
期刊：
影响因子：
9.2
通讯作者：
JAMI, J
中科院分区：
文献类型：
--
作者：
CORCOS, D;DUNDA, O;JAMI, J
工作背景：重链疾病（HCD）是人类淋巴组织增生性肿瘤，其特征在于分泌缺乏轻链的截短的免疫球蛋白重链。我们以前曾提出过类似的过程，突变的生长因子受体可以致癌-因为在HCDs的遗传缺陷导致的异常膜相关的重链缺乏抗原结合域的生产，这些异常的B细胞抗原受体可能参与配体非依赖性信号。正常的前B细胞发育需要前B细胞受体的存在，前B细胞受体由CL重链与两种多肽-所谓的替代轻链V-前B和λ 5 -结合形成，这两种多肽分别与免疫球蛋白轻链的可变和恒定部分同源。为了评估是否氨基端截断膜相关的重链的结果在其组成性激活，我们已经研究了一个HCD相关的μ蛋白，以促进前B细胞的转基因migrations.Results的发展能力：当μ HCD转基因被引入到SCID小鼠，CD 43（-）前B细胞正常发展。为了确定这种前B细胞发育是否需要替代轻链，我们将表达全长或截短的mu转基因的小鼠与λ 5缺陷小鼠回交。我们的研究结果表明，截短的重链，而不是正常的链，是能够促进前B细胞的发展，在λ 5的情况下。我们还表明，截短的mu链自发聚集在骨髓cells.Conclusions的表面：截短的mu重链的表达覆盖了严格控制的前B细胞发育的步骤，这强烈表明，组成性信号是由截短的mu链疾病蛋白。自聚集的μ链疾病蛋白可能占这种组成性激活。我们的结论是，氨基末端截断重链可能发挥作用的HCD瘤的发生，如果它发生在一个适当的阶段的B细胞分化，即在一个成熟的B细胞。
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 CL heavy chains with two polypeptides - so-called surrogate light chains, V-pre-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.