Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain
- Harvard Medical School, United States
- Perelman School of Medicine at the University of Pennsylvania, United States
Abstract
Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1's role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical 'developmental tumor', NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation.
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Animal experimentation: All zebrafish studies and maintenance of the animals were performed in accordance with Dana-Farber Cancer Institute IACUC-approved protocol (#02-107).
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© 2016, He et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain
eLife 5:e14713.
https://doi.org/10.7554/eLife.14713
