Two new studies may lead to the development of more effective therapies for individuals with multiple myeloma (MM), a common and incurable blood cell cancer. The research, published by Cell Press in the August issue of the journal Cancer Cell, provides new insight into the molecular mechanisms that underlie aberrant NF-κB activity in MM tumor cells and underscores the relevance of the NF-κB signaling pathway as a target for MM therapy.
MM is a cancer of the plasma cell, a blood cell that produces antibodies to help the body fight off infections. Previous research implicates abnormal activation of the NF-κB signaling pathway as a key event in MM pathology. NF-κB target genes are known to be involved in cell proliferation and cell survival. Although there is significant overlap and interplay between them, there are two separate pathways that lead to activation of NF-κB, the classical pathway and the alternative pathway.
Constitutive activation of NF-κB to block apoptosis has been implicated in various types of cancer, but the molecular mechanisms involved are not well understood. Two separate research groups used a variety of sophisticated genomic techniques to examine mutations in hundreds of MM patient samples and cell lines to identify mutations that impact NF-κB activation.
Dr. Louis M. Staudt from the National Cancer Institute led a research group who revealed the importance of both the classical and alternative NF-κB pathways in MM pathogenesis. Most MM patient samples examined exhibited NF-κB pathway activation via diverse genetic abnormalities. Importantly, targeted disruption of the classical NF-κB signaling blocked myeloma proliferation and induced cell death. "These genetic and functional data provide a molecular framework for the rational development of NF-κB pathway inhibitors for the therapy of MM," offers Dr. Staudt.
In a separate study, Dr. Rafael Fonseca, from the Mayo Clinic Arizona, and colleagues report mutations in several genes that result in constitutive activation of the alternative NF-κB 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. Our results suggest a mechanism by which MM cells can overcome these limitations through acquisition of mutations that result in constitutive and ligand-independent activation of the alternative NF-κB pathway," explains Dr. Fonseca.
Taken together, results for these studies define diverse mutations that lead to pathological activation of NF-κB signaling in MM and describe a shift of plasma cells from dependence on the microenvironment to an environment-independent state during progression of MM. Regardless of the specific method of activation, the NF-κB pathway plays a central role in MM pathogenesis and is an excellent target for development of new therapeutics.
These articles are accompanied by a preview article written by Dr. Thomas D. Gilmore from Boston University.
Annunziata et al.
The researchers include Christina M. Annunziata, R. Eric Davis, Yulia Demchenko, Ana Gabrea, Georg Lenz, George Wright, Sandeep Dave, Elaine M. Hurt, Bruce Tan, Hong Zhao, W. Michael Kuehl, and Louis M. Staudt of the National Cancer Institute, Bethesda, MD; William Bellamy, Fenghuang Zhan, Ichiro Hanamura, Owen Stephens, Madhumita Santra, David R. Williams, Bart Barlogie, and John D. Shaughnessy, Jr. of the University of Arkansas for Medical Sciences, Little Rock, AR; Wenming Xiao of the National Institutes of Health, Bethesda, MD; Lenny Dang of Millennium Pharmaceuticals, Cambridge, MA.
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (L.M.S., W.M.K.); NIH grant CA55819 (B.B. and J.D.S.); and the Lebow Fund for the Cure (J.D.S.).
Keats et al.
The researchers include Jonathan J. Keats, Rafael Fonseca, Marta Chesi, Roelandt Schop, Wee-Joo Chng, Scott Van Wier, Rodger Tiedemann, Chang-Xin Shi, Michael Sebag, Esteban Braggio, Travis Henry, Yuan-Xiao Zhu, Homer Fogle, Gregory Ahmann, Riccardo Valdez, A. Keith Stewart, and P. Leif Bergsagel of Mayo Clinic Arizona, Scottsdale, AZ; Tammy Price-Troska, Shaji Kumar, Philip Greipp, and Angela Dispenzieri of Mayo Clinic, Rochester, MN; Angela Baker, Catherine Mancini, Michael Barrett, Jeff Trent, and John Carpten of Translational Genomics, Phoenix, AZ; Leslie A. Brents of National Cancer Institute, Bethesda, MD; Barb Bryant and George Mulligan of Millennium Pharmaceuticals, Cambridge, MA; Laurakay Bruhn of Agilent Technologies, Santa Clara, CA.
This work was supported by grants R01-AG020686 (P.L.B.), R01-CA83724-01 (R.F.), SPORE P50-CA100707-01 (R.F. and P.L.B.) and P01-CA62242 (R.F.) from the National Cancer Institute, and the Donaldson Charitable Trust Fund (R.F.).
Keats et al.: "Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma." Publishing in Cancer Cell 12, 131-144, August 2007, DOI 10.1016/j.ccr.2007.07.003. http://www.
Annunziata et al.: "Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma." Publishing in Cancer Cell 12, 115-130, August 2007, DOI 10.1016/j.ccr.2007.07.004. http://www.cancercell.org