Pre-B-cell development in the absence of λ5 in transgenic mice expressing a heavy-chain disease protein

AbstractBackground: 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 μ heavy chains with two polypeptides — so-called surrogate light chains, Vpre-B and λ5 — 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 μ protein to promote pre-B-cell development in transgenic mice.Results When the μ 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 μ transgenes with λ5-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 λ5. We also show that truncated μ chains spontaneously aggregate at the surface of bone marrow cells.Conclusion Expression of the truncated μ heavy chain overrides a tightly controlled step of pre-B-cell development, which strongly suggests that a constitutive signal is delivered by the truncated μ chain disease protein. The self-aggregation of μ 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

Haplotypes in Tribal Indians Bearing the Sickle Gene: Evidence for the Unicentric Origin of the ßs Mutation and the Unicentric Origin of the Tribal Populations of India

To determine the origin of sickle cell anemia (SS) in India, we analyzed haplotypes of the ß gene cluster in ßs-carrying individuals belonging to tribal populations living in the Nilgiris region of southern India and complemented the available data on tribes of east-central India. We found that in the Nilgiris tribes chromosomes bearing the ßs gene are linked in 91% of the cases to the “Asian” (Arab-Indian) haplotype (although 25% of the haplotypes had the c polymorphic site negative, making the 5\u27 portion of the haplotype identical with the African Senegal haplotype). These XmnI (+) chromosomes were associated with high Gɿ expression (67.2 ± 5.9%) and a high percentage of Hb F (15.5 ± 7.9%; range, 6-25.3%). We have similar findings for tribal groups from west-central India (Gujarat). In east-central India we have confirmed the data of others, finding the same haplotype linked to ßs in tribes living in the east (Orissa, Andhra Pradesh). We conclude that the ßs gene in presently isolated and disperse tribal populations in India is associated with one predominant typical haplotype, suggesting a unicentric origin of the mutation in India. In addition, this finding implies a unicentric origin of the tribal populations themselves: The gene must have arisen and spread before tribal dispersion. Furthermore, we find extremely high frequencies of the (—α) haplotype in the Nilgiris (0.89) and in Gujarat (0.95). The ßs gene linkage to a high Hb F-expressing haplotype and the high incidence of α-thalassemia predict a mild phenotypical expression of sickle cell anemia in India