Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo.

BACKGROUND

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with complex molecular and genetic alterations. Powerful tumor suppressors and are commonly disrupted along with , a gene that encodes a negative regulator of Ras. Many additional factors have been implicated in MPNST pathogenesis. A greater understanding of critical drivers of MPNSTs is needed to guide more informed targeted therapies for patients. RABL6A is a newly identified driver of MPNST cell survival and proliferation whose role in the disease is unknown.

METHODS

Using CRISPR-Cas9 targeting of or in the mouse sciatic nerve to form MPNSTs, we investigated the biological significance of RABL6A in MPNST development. Terminal tumors were evaluated by western blot, qRT-PCR, and immunohistochemistry.

RESULTS

Mice lacking displayed slower tumor progression and extended survival relative to wildtype animals in both genetic contexts. YAP oncogenic activity was selectively downregulated in -null, lesions whereas loss of RABL6A caused upregulation of the CDK inhibitor, p27, in all tumors. Paradoxically, both models displayed elevated Myc protein and Ki67 staining in terminal tumors lacking RABL6A. In tumors, cellular atypia and polyploidy were evident and increased by RABL6A loss.

CONCLUSIONS

These findings demonstrate that RABL6A is required for optimal progression of NF1 mutant MPNSTs in both and inactivated settings. However, sustained RABL6A loss may provide selective pressure for unwanted alterations, including increased Myc, cellular atypia, and polyploidy, that ultimately promote a hyper-proliferative tumor phenotype akin to drug-resistant lesions.