PgmNr Z6003: Synergy between Loss of NF1 and Overexpression of MYCN in Neuroblastoma Is Mediated by the GAP-related Domain.

Authors:
Shuning He 1 ; Marc R. Mansour 1,2 ; Mark W. Zimmerman 1 ; Dong Hyuk Ki 1 ; Hillary M. Layden 1 ; Koshi Akahane 1 ; Eric D. de Groh 3 ; Antonio R. Perez-Atayde 4 ; Shizhen Zhu 5 ; Jonathan A. Epstein 3 ; A. Thomas Look 1


Institutes
1) Dana-Farber Cancer Institute, Boston, MA; 2) University College London, London, UK; 3) Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 4) Children's Hospital Boston, Boston, MA; 5) Mayo Clinic, Rochester MN.


Abstract:

Earlier reports have shown that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1’s role in down-modulating RAS-MAPK signaling.  By contrast, loss of nf1 leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and the activity of the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the accelerated onset of neuroblastoma in nf1-deficient zebrafish.  Thus, even though neuroblastoma is a classical “developmental tumor” of childhood, NF1 uses 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 the MEK inhibitor trametinib and the retinoid isotretinoin in vivo in primary 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.



ZFIN Genetics Index
1. nf1a
2. nf1b
3. dbh