DIPG-06. IDENTIFICATION OF GENES FUNCTIONALLY INVOLVED IN THE DETRIMENTAL EFFECTS OF MUTANT HISTONE K27M-H3.3 USING DROSOPHILA MELANOGASTER. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Berlandi, Johannes; Chaouch, Amel; Tegeder, Isabel; Thiel, Katharina; Kleinman, Claudia L; Shirinian, Margret; De Jay, Nicolas; Jeibmann, Astrid; Lasko, Paul; Jabado, Nada; Hasselblatt, Martin
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i50
• Page End: i50
• Publication Date: 2018-06-22
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy059.100
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Histone H3 mutations (K27M, G34R and G34V) have been identified as driver mutations in malignant gliomas, but little is known about targetable downstream signaling pathways. We thus aimed at identifying genes playing a functional role in the detrimental effects of histone H3 mutations using a Drosophila model. Ubiquitous and midline glia specific expression of K27M-H3.3 (but not wildtype H3.3) caused pupal lethality, morphological alterations and decreased H3K27me3. In Gal4/UAS modifier screens, shRNA knockdown of 17/194 candidate genes resulted in a positive shift of lethality to later stages of development. These included genes encoding histone modifying and chromatin remodeling proteins as well as downstream genes regulating cell differentiation and proliferation. Single sample gene set enrichment analysis revealed human orthologues of candidate genes to be enriched in K27M-H3-mutant diffuse midline gliomas. Three candidate genes, i.e. HMGB2, BMI1 and ELP3 were significantly over-expressed in K27M-H3-mutant diffuse midline gliomas. These results suggest that fly models can be employed for the identification of functionally relevant genes involved in the detrimental effects of mutant histone H3. Supported by IZKF Münster (Ha3/019/15)