Mutations of c-myc May Play Role in Myeloma Progression

MIAMI BEACH—By conventional karyotyping, the frequency of c-myc dysregulation in multiple myeloma is low. Now, using molecular karyotyping techniques, researchers have found c-myc chromosomal abnormalities in multiple myeloma cell lines.

“We have screened genomic DNA from 20 multiple myeloma cell lines in our lab for mutations in c-myc exons, and in six of these, we have found two genetically distinct c-myc alleles—a normal wildtype allele plus a polymorphic allele containing a silent mutation,” said Yaping Shou, MD, PhD, of the National Cancer Institute, Medicine Branch. “Although c-myc is overexpressed in all six of these cell lines, only one c-myc allele is expressed,” Dr. Shou told Oncology News International at a poster session of the 40th annual meeting of the American Society of Hematology (ASH) .

The researchers have also analyzed the corresponding primary tumor cells in one of the six mutated cell lines and found only one c-myc allele to be selectively expressed. By contrast, in three B lymphoblastoid cell lines, both c-myc alleles are expressed to a similar extent.

By conventional karyotyping, the researchers could find no structural alteration of c-myc locus in the six multiple myeloma cell lines with a mutation. Dr. Shou and her colleagues at the NCI, National Center for Genome Research, and Cornell University Medical College then began screening these cell lines for chromosomal abnormalities using more sensitive fluorescent in situ hybridization (FISH) (see Figure) and spectral karyotyping (SKY) analysis.

In the three cell lines examined to date by these techniques, translocations involving the c-myc locus at 8q24 have been identified. The partner chromosomes of these translocations include chromosome 14 in the JJN3 cell line, chromosome 1 in OPM2, and an unknown chromosome in MM1-144. “It makes sense that the translocated c-myc allele is the allele that is expressed in most multiple myeloma cell lines,” Dr. Shou said.

When Do Translocations Occur?

Dr. Shou said that the researchers need to finish screening their cell lines for c-myc translocations and also determine the frequency of c-myc translocations in myeloma patients and when during myeloma development the translocations occur.

She pointed out that most of the cell lines her group is studying are from the final leukemic stage of multiple myeloma, “so we think c-myc probably is important, not for tumor formation, but for tumor development to the leukemic stage.”

If it turns out to be true that c-myc translocation occurs only in the final stage of the disease, she said, then researchers could attempt to develop a therapeutic approach, possibly by antisense technology, to block c-myc overepression, which in theory could stop or slow tumor development to the final stage.