Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [CUT&Tag]

Diffuse intrinsic pontine glioma (DIPG), an exceptionally lethal pediatric cancer with limited treatment options, is characterized by relentless proliferation and differentiation arrest, primarily influenced by H3K27M oncohistones. This study unveils that ID1 activation occurs independently of BMP signaling in H3.3K27M/ACVR1WT DIPG subtype. ID1 inhibition promotes cell differentiation and apoptosis in DIPG. Additionally, we discover the intricate regulation of ID1 tied to the lineage-specific transcription factor CREB5—an oncogenic contributor hindering differentiation in the H3.3K27M subtype of DIPG. The SWI/SNF complex is identified as a co-regulator of CREB5, further promoting tumorigenesis. Intriguingly, H3.3K27M oncohistones act as a trigger for CREB5 overexpression, facilitating the formation of super-enhancer promoter loops. Moreover, our research highlights the potent anti-tumor effect of ABBV-075 in treating DIPG. In essence, this study elucidates the oncohistone-driven H3.3K27M/CREB5/ID1 axis, providing insights into the malignant cellular state within a DIPG subtype and offering potential therapeutic avenues for this devastating pediatric cancer.