DNA Hypomethylation Is Not Cell Intrinsically Toxic to Polycomb Repressive Complex 2 Deficient Malignant Peripheral Nerve Sheath Tumors

ABSTRACT

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas and the most common cause of disease‐associated death for neurofibromatosis type 1 (NF1) patients. In the context of NF1, MPNSTs develop from benign premalignant precursors and the transition to malignancy is typically accompanied by loss of the polycomb repressive complex 2 (PRC2), which results in aberrant upregulation of over 1200 genes due to global depletion of histone H3 lysine 27 trimethylation (H3K27me3). Previous studies suggest cells compensate for the loss of this repressive histone mark via hypermethylation of the genome. Here we analyzed genome‐wide DNA methylation and the transcriptome in MPNST cell lines and isogenic PRC2‐deficient and ‐proficient CRISPR‐engineered immortalized human Schwann cells. In addition to effects of PRC2 status, we also measured the effects of two DNA methyltransferase inhibitors (DNMTi), decitabine and azacitidine. We found that PRC2 status does not affect global DNA methylation or average methylation levels across specific genomic features. Furthermore, decitabine and azacitidine have differential effects on MPNSTs. While both DNMTis hypomethylate the genome, they upregulate different targets. Azacitidine upregulates genes involved in RNA processing pathways and exhibits direct tumor cell cytotoxicity, while decitabine upregulates genes involved in the immune response, has no direct‐cell killing effects, and likely suppresses tumor growth in vivo by altering the tumor microenvironment. We show that DNA hypomethylation alone is insufficient to kill MPNST cells, regardless of PRC2 status. Consequently, these findings suggest that DNMT inhibitors should be utilized in combination with other targeted therapies for MPNST patients.