ID #407 Identification of SETD2 as a potential therapeutic target in diffuse midline glioma

Abstract

Diffuse midline gliomas (DMGs) are aggressive brain cancers that are currently incurable and carry a dismal prognosis. Most DMGs are driven by lysine-to-methionine substitution at position 27 in Histone H3 (H3-K27M). Beyond this hallmark lesion, DMGs are characterized by substantial genetic and molecular heterogeneity. This suggests that distinct tumors may be vulnerable to different therapeutic interventions. To identify potential therapeutic targets, we performed functional genomic screens in a panel of DMG cell lines, using a CRISPR library targeting around 3000 genes encoding “druggable” molecules. We observed that multiple cell lines were sensitive to the targeting of SETD2, which encodes an enzyme that trimethylates lysine 36 on H3 (H3-K36me3). Orthogonal screens performed by the Childhood Cancer Model Atlas confirmed these observations, highlighting that about 40% of pediatric-type high-grade glioma cell lines are sensitive to the loss of SETD2. To elucidate the consequences of perturbing SETD2, we profiled the transcriptomic and epigenetic changes caused by SETD2 knockout in DMG cells. Interestingly, we observed down-regulation of key developmental genes that define neural progenitor cells, which are normally over-expressed in DMGs. Consistently, SETD2 knockout caused epigenetic remodeling, and its effects on DMG cell growth or viability were at least partially dependent on the presence of H3-K27M. Overall, our results nominate SETD2 as a potential therapeutic target in a substantial proportion of DMGs.