Inactivation of the E3/LAPTm5 gene by chromosomal rearrangement and DNA methylation in human multiple myeloma

Abstract

Chromosomal band 1p34-36 is a commonly rearranged locus in many types of cancers. We cloned the breakpoint region of a chromosomal translocation, t(1;14)(p34;q32), found in the human multiple myeloma (MM) cell line, ODA. This rearrangement occurred between the nearby switch region of the immunoglobulin heavy chain (IgH) gene (Sc3) at 14q32 and the first intron of the human retinoic acid-inducible E3 protein (E3)/lysosomeassociated protein, transmembrane-5 (LAPTm5) gene at the 1p34 locus. Consequently, the E3 gene, which is a hematopoietic cell-specific transcript induced by retinoic acid and located at the rearranged allele, was interrupted within its coding region and was not expressed in the ODA cell line in spite of the other allele still being intact. The expression derived from the remaining intact allele in ODA cells was silenced by DNA methylation at sequences within the first intron around a GC-rich EagI site. Interestingly, the silenced expression of E3 mRNA due to DNA methylation of intron 1 sequences was frequently encountered in MM cells [6/10 (60%) of MM cell lines tested], while E3 is expressed in normal plasma cells and in most other hematopoietic cell lines including those of B-cell lineage. Thus, as the E3 protein has been suggested to be involved in cellular differentiation and apoptotic pathways in certain cell types, our results suggest that loss of E3 gene expression might be a crucial event during the progression of human MM.

Functional Proteomics Mapping of a Human Signaling Pathway

“…GCD-10, the LAPTm5 ortholog in rats, was found to be activated in response to neuronal apoptosis (Origasa et al 2001). Recently, inactivation of the LAPTm5 gene was observed in human multiple myeloma (Hayami et al 2003). Although this protein is structurally related to a family of lysosomal transporter proteins that regulate cellular multidrug resistance (Cabrita et al 1999), its function remained unknown.…”

A Lysosomal Protein Negatively Regulates Surface T Cell Antigen Receptor Expression by Promoting CD3ζ-Chain Degradation

“…Are there any human immunodeficiencies or autoimmune diseases that are associated with dysregulated LAPTM5 function? It is interesting to note that Laptm5 gene is inactivated by either chromosomal deletion or promoter methylation in four cases of human multiple myeloma (Hayami et al, 2003), raising the possibility that LAPTM5 may also have a tumor-suppressor function in humans.…”

High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in AML and MDS cases with trisomy 8 as the sole cytogenetic aberration

“…Of these, three -the duplicated LAPTM5 and HSH2D (ALX) and the hemizygously deleted CD28 -have been shown to be involved in hematopoiesis and/ or hematologic malignancies. 32,33 In conclusion, the present array CGH analysis revealed cryptic chromosome changes in nine of 10 AML/MDS cases with trisomy 8 as the sole cytogenetic abnormality. Excluding imbalances overlapping with previously described CNPs, novel -and possibly leukemia-associated -aberrations were found in four (40%) of the cases.…”