A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma:: A novel mechanism of oncogene de-regulation

The 5' untranslated region of the proto-oncogene c-myc contains an internal ribosome entry segment (IRES) (Nanbru ct nl,, 1997; Stoneley ct al., 1998) and thus c-myc protein synthesis can be initiated by a cap-independent as well as a cap-dependent mechanism (Stoneley ct al., 2000), In cell lines derived from patients with multiple myeloma (RIM) there is aberrant translational regulation of c-myc and this correlates with a C-T mutation in the c-myc-IRES (Paulin ct nl,, 1996), RNA derived from the mutant IRES displays enhanced binding of protein factors (Paulin ct nl,, 1998), Here we show that the same mutation is present in 42% of bone marrow samples obtained from patients with MM, but was not present in any of 21 controls demonstrating a strong correlation between this mutation and the disease. In a tissue culture based assay, the mutant version of the c-myc-IRES was more active in all cell types tested, but showed the greatest activity in a cell line derived from a patient with MM. Our data demonstrate that a single mutation in the c-myc-IRES is sufficient to cause enhanced initiation of translation via internal ribosome entry and represents a novel mechanism of oncogenesis.