New evidence on the molecular mechanisms that underlie aberrant NF-kB activity in multiple myeloma (MM) tumor cells has been found by two separate groups of scientists. Taken together, results define diverse mutations that lead to pathological activation of NF-kB signaling in MM and describe a shift of plasma cells from dependence on the microenvironment to an environment-independent state during progression of MM.
Louis M. Staudt, M.D., Ph.D., from the NCI, reports research that shows the importance of both the classical and alternative NF-kB pathways in MM pathogenesis. Most MM patient samples examined exhibited NF-kB pathway activation via diverse genetic abnormalities. Additionally, they found that targeted disruption of the classical NF-kB signaling blocked myeloma proliferation and induced cell death.
The NCI team discovered that a small molecule inhibitor of IkB kinase beta (IKK beta) targeting the classical NF-kB pathway was lethal to many myeloma cell lines. They studied its effects in 21 cell lines with different molecular subgroups of MM. Moderate-to-high sensitivity was observed in 12, intermediate sensitivity in three, and six were resistant. Cell lines showed varying degrees of apoptosis and growth arrest in response to IKK beta inhibition.
In a separate study, Rafael Fonseca, M.D., from the Mayo Clinic Arizona, and colleagues report mutations in several genes that result in constitutive activation of the alternative NF-kB pathway. “We propose that the acquisition of the mutations identified in our study results in the accumulation of malignant plasma cells beyond the physiological control of the bone marrow compartment.”
The investigators profiled 155 multiple myeloma samples and identified abnormalities in approximately 20% of patients. They report mutations in 10 genes, with the single most common abnormality being inactivation of TRAF3.
Both studies are published in the August issue of Cancer Cell.