Although epigenetic cell differentiation mechanisms remain challenging pharmacologic targets24, we find NF2 inactivation in NF1-mutant, PRC2-intact neurofibroma cells leads to PAK activation, underlies de-differentiation, and correlates with selumetinib resistance in NF1-mutant Schwann cell tumors, elucidating a druggable dependency for combination molecular therapy (Fig. 3f). This evidence concerns the gene NF2 and neurofibroma.