DIPG-39. ONCOHISTONE H3.3K27M-DRIVEN CREB5/ID1 AXIS DICTATES THE MALIGNANT CELL STATES OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric cancer characterized by the presence of H3K27M-oncohistones, which drive relentless proliferation and differentiation arrest. This study focuses on the H3.3K27M DIPG subtype and investigates the role of the oncohistone-driven CREB5/ID1 axis in promoting malignancy. METHODS We employed a variety of biological in vitro assays and xenograft mouse models utilizing several H3.3K27M and H3.1K27M DIPG cell lines to evaluate the impact of the studied factors on the growth of DIPGs. Additionally, we employed methodologies in molecular biology, bioinformatics, drug screening, and biochemistry to elucidate the underlying mechanisms of tumorigenesis. RESULTS Through inhibition of ID1, this study explores the induction of cellular differentiation and apoptosis in H3.3K27M DIPG, shedding light on the oncogenic mechanisms at play. The intricate regulation of ID1, linked to CREB5—an oncogenic contributor independent of BMP signaling—is elucidated. The involvement of the SWI/SNF complex as a co-regulator of CREB5 is also examined. Moreover, our findings reveal that H3.3K27M-oncohistone triggers CREB5 overexpression, facilitating the formation of a super-enhancer promoter loop at the CREB5 locus. Disruption of this loop demonstrates potent anti-tumor efficacy in treating DIPG. Additionally, the combination of a compound targeting the CREB5/ID1 axis and a BRG1 inhibitor shows promise for DIPG treatment. CONCLUSIONS This research unveils key molecular pathways specific to the H3.3K27M DIPG subtype, offering valuable insights for potential therapeutic interventions against this lethal pediatric cancer. Inhibiting the CREB5/ID1 axis represents a promising strategy for inducing differentiation and apoptosis in DIPG cells, highlighting the potential for targeted therapies in combating this disease.