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.

Pleased to present at #ESMO25 the 16 year experience of tandem high-dose chemotherapy and autologous stem cell transplant for relapsed/refractory advanced stage germ cell tumours from Princess Margaret Cancer Centre, Toronto 🇨🇦

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].

Looking forward to sharing collaborative work by myself and @dr-chromatin.bsky.social from the labs of @adrianbracken.bsky.social and @conwayer1.bsky.social at #ASH24 in San Diego this week. #hemesky #lymsm please feel free to stop by and share your thoughts.