Thank you especially to PI Prof Michael Crump, co-authors in the LMT Group (Prof John Kuruvilla , Dr Anca Prica, Dr Abi Vijenthira, Dr Sita Bhella, Dr Robert Kridel), GU Group (Prof Philippe Bedard , Dr Di Maria Jiang, Dr Esmail Al-Ezzie, Dr Robert Hamilyon), Prof Pádraig Warde & Prof Malcolm Moore

Despite favourable data for cohort overall, patients with platinum refractory disease prior to ASCT had a PFS of <6 months, highlighting a population with a significant unmet need for alternative strategies

A total of 123 transplants completed. With median 6.4 year follow-up, median PFS/OS not reached with 2-year PFS and OS 52.1% and 73.4%. No progression events after 2 years.

16/ This work complements our previous research on CBX4 and H3K27M-mutant DMG [https://tinyurl.com/ev6drrya], showing how different forms of PRC2 dysfunction can be targeted in distinct cancer contexts. 🔍

15/ We believe our findings offer significant insights for both basic and clinical research. By understanding the role of H3K27me2 in PRC2 dysfunction, we can explore new treatments for EZH2-dependent cancers. 🏥

14/ In fact, we also show that targeting AEBP2 can overcome two distinct mechanisms of resistance to EZH2 inhibitors in vitro, a finding with important therapeutic implications. 💊

13/ Why does this matter? Our study reveals how AEBP2 regulates H3K27me2 at intergenic regions, offering a new view of PRC2 dysfunction in cancer. This provides new therapeutic opportunities by targeting AEBP2 in cancers resistant to PRC2 inhibitors! 💡

12/ AEBP2 likely acts downstream of PCGF5 (a variant PRC1 member), which is responsible for depositing H2AK119ub1 at intergenic regions. Interestingly, we also show that PCGF5 loss also sensitizes cells to PRC2 inhibitors. 🔄

11/ Mechanistically, we show that the ZF2 domain of AEBP2 is essential for its ability to bind chromatin and promote PRC2 mediated H3K27me2 at intergenic regions.

10 / We used sgRNA-tiled CRISPR screens to pinpoint the 3 zinc fingers of AEBP2 as being essential for its function in EZH2-mutant lymphoma! 🧬

9/ Mechanistically, in lymphoma, AEBP2 functions within a unique PRC2.2 complex that lacks JARID2, making it less tethered to CpG islands at Polycomb target genes.

8/ Our key finding: H3K27me2 is central to both sensitivity and resistance to PRC2 inhibitors. Loss of NSD2 increases H3K27me2, while loss of AEBP2 reduces it in EZH2-mutant lymphoma. This could explain why some cancers are resistant to treatment. ⚖️

7/ We also found that loss of NSD2 (responsible for mediating H3K36me2) increases H3K27me3 yet, unlike loss of AEBP2, its loss confers resistance to PRC2 inhibitors. This led us to focus on the underexplored H3K27me2 modification! 🔬

6/ Unlike loss of core PRC2 components, the loss of AEBP2 increases H3K27me3 levels without derepressing Polycomb target genes. AEBP2 acts differently from other PRC2 components in regulating chromatin, making it an exciting new target in cancer. 🧫

5/ We identified the PRC2 accessory component AEBP2 as a genetic dependency in EZH2-mutant lymphoma via a CRISPR screen, but interestingly, this dependency isn't observed in other PRC2-dependent cancers such as malignant rhabdoid tumors or H3K27M-mutant DMG [https://tinyurl.com/ev6drrya].

4/ In this study, we discover a new form of PRC2 dysfunction in cancer - distinct from canonical PRC2-mediated H3K27me3 associated repression - that modulates sensitivity and resistance to PRC2 inhibitors. Specifically, we find it involves deregulation of H3K27me2 at intergenic chromatin regions. 🧬

3/ Thanks to many others across @tcddublin.bsky.social, @ucddublin.bsky.social, @uniofgalway.bsky.social, @mayoclinic.org, and Trinity St. James’s Cancer Institute, and to our generous funders Irish Cancer Society and @worldwidecancer.bsky.social.

2/ Firstly, this was a fantastic collaborative effort that would not have been possible without super-talented co-first author @dr-chromatin.bsky.social, and co-senior authors @conwayer1.bsky.social and @adrianbracken.bsky.social.