High Expression of Membrane Cofactor Protein of Complement (CD46) in Human Leukaemia Cell Lines: Implication of an Alternatively Spliced Form Containing the ST^A Domain in CD46 Up‐Regulation

Abstract

Human membrane cofactor protein (MCP, CD46) is a receptor for the measles virus and serves as a complement regulator which protects host cells from autologous complement attack. MCP is highly polymorphic due to a variety of mRNA splice products. The levels of MCP expression on T and myeloid cell lines are usually two-eightfold higher than those on their normal counterparts, whereas Burkitt's lymphoma B cell lines express less MCP than B cell lineages carrying no EB virus. The molecule has a Ser/Thr-rich (ST) domain adjacent to the functional domain, namely short consensus repeats (SCR). The ST domain and a cytoplasmic tail (CYT) contribute to the MCP polymorphism. The ST domain is encoded by three exons (A, B and C) and major ST isoforms are STABC, STBC and STC. The authors investigated the relationship between the expression levels and isoform usage of MCP by flow cytometry using specific antibodies against STA and STC, by reverse transcriptase-polymerase chain reaction (RT-PCR) with size markers for each splice variant, and by RT-PCR/Southern blotting using a specific probe for STA. The results were (1) the profiles of mean shifts of myeloid and T cell lines were STC < STA on flow cytometry while those of B cell lines and normal blood cells were STA < STC; (2) all cell lines tested by RT-PCR expressed the messages for the isoforms STBC/CYT1, STC/CYT1, STBC/CYT2, and STC/CYT2. The band for STABC/CYT2 overlapped that for STC/CYT1, and the band for STABC/CYT1 was marginal in all cell lines examined; (3) semi-quantitative analysis of the STABC isoforms by Southern blotting indicated the presence of high levels of the STABC messages in myeloid and T-cell lines in comparison with B lymphoid cells and normal leucocytes. Thus, the quantity of MCP expressed parallels the STABC message level, which is up-regulated in T and myeloid leukaemia cell lines.

Quantitation of human herpes virus 6 genome in children with acute lymphoblastic leukemia

“…The wide distribution of HHV-6 in vitro and in vivo is consistent with the ubiquitous nature of its receptor, CD46 [Santoro et al, 1999]. The expression of the CD46 receptor is also found on malignant cells and particularly on leukemia cells [Hara et al, 1995]. However, CD46 is not sufficient by itself to enable HHV-6 fusion, thus the virus might require an additional factor, possibly a viral co-receptor, to make cells permissive to infection.…”

Quantitative analysis of human herpesvirus-6 genome in blood and bone marrow samples from Tunisian patients with acute leukemia: a follow-up study

“…The cellular receptor of HHV-6 is CD46, expressed on the surface of normal and malignant cells as well as on leukemic cells [4]. HHV-6 oncogenic potential was demonstrated in vitro in NIH3T3 cells [5], and ORF-1, also referred to as DR7, was identified as an oncogene.…”

Measles

“…The expression ratio of the four main isoforms is inherited in an autosomal codominant fashion, with three phenotypes in the population: the majority (65%) expresses predominantly the highly O -glycosylated BC1/2 forms, 6% express predominantly the less glycosylated C1/2 forms, and 29% of the population express both forms in roughly equal amounts (Liszewski et al 1991;Wilton et al 1992;Seya et al 1999). The carboxyl terminus of CD46 is also differentially spliced, giving rise to two distinct cytoplasmic tails, designated CYT-1 (16 amino acids) and CYT-2 (23 amino acids) 3 Measles Virus and CD46 35 EBV-transformed lymphocytes and leukemic cell lines (ABC1/2) and in the placenta (B1/2) (Hara et al 1995;Matsumoto et al 1992;Russell et al 1992;Purcell et al 1991;Johnstone et al 1993), has not been identified. Soluble forms of CD46, possibly shed from the cell surface via metalloproteinases (Hakulinen and Keski-Oja 2006), are present in low concentrations in plasma, seminal fluid, and tears (Hara et al 1992;Simpson and Holmes 1994).…”