Neurofibromatosis-1 (NF1) is an inherited disorder caused by mutations in the NF1 gene. This results in the formation of nervous tissue tumors (neurofibromas) in the skin, subcutaneous tissue, and the cranial and spinal root nerves.
Additionally, NF1 patients are predisposed to juvenile myelomonocytic leukemia (JMML), myeloproliferative disorders, and malignant peripheral nerve sheath tumors (MPNST). NF1 encodes a protein that serves as a negative regulator of a signaling pathway composed of RAS, RAF, MEK, and ERK proteins, known as MAPK signaling cascades. Cells expressing mutated NF1 exhibit hyperactivation of these signaling pathways.
In this issue of the Journal of Clinical Investigation
, three independent groups of researchers report that MAPK hyperactivation is a critical mediator of disease pathogenesis in neurofibromatosis. Researchers led by Wade Clapp at Indiana University found that disruption of ERK signaling blocked the development of JMML in NF1 mutant mice.
Similarly, Kevin Shannon and colleagues at the University of California, San Francisco, determined that inhibition of the MAPK signaling cascade component, MEK, reduced the growth of NF1-associated peripheral nerve tumors in mice. MEK inhibition was also shown to ameliorate NF1-associated murine myeloproliferative disorders by Nancy Ratner's research group at Cincinnati Children's Hospital Medical Center. Taken together, these studies demonstrate that hyperactivation of MEK and ERK underlies NF1-associated disorders and provide a rationale for testing MEK and ERK inhibitors in neurofibromatosis patients.