A study of c-myc translational regulation in multiple myeloma

In cell lines derived from patients with multiple myeloma (MM), a B-cell neoplasia, a 10-20 fold elevation in the level of c-myc protein has been observed. This was not accompanied by a concomitant increase in c-myc mRNA levels and there was no alteration in the half life of the protein suggesting that a translational mechanism could be responsible for the elevated c-myc protein levels.;Sequence analysis of c-myc exon 1, a region previously implicated in translational control, revealed no gross sequence abnormalities of the c-myc gene in the MM cell lines. However, in 4 out of 5 MM cell lines examined, a consistent CT transition at position 2756 was observed. This mutation was not seen in any control cell lines or in peripheral blood samples derived from healthy patients implying that the sequence alteration is not merely a polymorphism of this locus and may be associated with the malignant phenotype. Additionally, the MM cell line which did not possess the mutation displayed atypical antigenic expression.;Examination of proteins binding to the c-myc 5'UTR revealed a large number of proteins with this capacity. In addition, the mutant sequence displayed enhanced binding affinity to proteins, specifically polypeptides of 98 and 38 kD. Differences in RNA binding factors were also detected between the control and MM cell lines.;c-myc exon 1 was found to inhibit the translation of heterologous reporter genes in vitro. However, this region was also found to be capable of promoting the internal initiation of ribosomes in dicistronic reporter constructs. Moreover, the mutant sequence displayed an augmented capacity for internal initiation of translation.;Both the mutation and altered protein factors in the multiple myeloma cell lines thus appear to affect the translational efficiency of c-myc mRNA and their combinatorial effects may be sufficient to account for the elevated levels of c-Myc observed.