Interesting thought!

Thank you to all the contributors in the Wagenblast lab (especially Ke Wang, Shayan Saniei and Nikita Poddar), all our collaborators and funding mechanisms. @eirinipapapetrou.bsky.social

Key takeaway: WHEN mutations arise profoundly impacts leukemia aggressiveness & treatment responses. Targeting fetal-specific vulnerabilities holds exciting potential for pediatric AML. Read the full pre-print here: www.biorxiv.org/content/10.1... 13/13

Leveraging fetal NUP98::NSD1’s reliance on BCL2 & oxidative phosphorylation, we tested Venetoclax combinations (with Ara-C or Revumenib). Result: dramatically reduced leukemia in mice. Could this combo redefine pediatric AML therapy? 12/13

Clinically, pediatric AML patients with our fetal-oncogenic signatures had significantly worse outcomes. This signature could help identify high-risk patients, highlighting opportunities to personalize therapies early. 11/13

PRDM16 emerged as a master regulator in fetal-origin NUP98::NSD1 AML. Knocking out PRDM16 halted leukemia growth and overcame therapy resistance, spotlighting PRDM16 as an exciting therapeutic target. 10/13

Fetal-origin leukemia stem cells uniquely rely on oxidative phosphorylation & fatty acid oxidation, driven by the transcription factor PRDM16. PRDM16 also enhances anti-apoptotic BCL2, creating powerful therapy resistance. 9/13

Leukemias responded differently to chemotherapy (Ara-C) & menin inhibition (Revumenib) based on developmental origin. Postnatal cord blood-derived AML responded better to Revumenib; fetal-origin AML was more resistant. Why this difference? 8/13

Indeed, fetal-origin LMPP/early GMP cells were highly enriched for the leukemia stem and progenitor (LSPC) QUIESCENT signature, while cord blood-derived AML was enriched for the LSPC CYCLING signature. 7/13

Single-cell RNA & chromatin accessibility profiling revealed WT1 loss expands early progenitors (LMPP/early GMP), enriched for quiescence (high EGR1) & high MYC expression. Could this explain increased leukemia aggressiveness? 6/13

In mice, these engineered cells formed aggressive AML. Adding WT1 loss-of-function intensified disease severity, boosting leukemia stem cell traits and therapy resistance. WT1 loss marks exceptionally aggressive AML subsets. 5/13

With GoT-ChA (single-cell ATAC-seq + genotyping), fetal-derived NUP98::NSD1 cells revealed strong enrichment for HOX genes, MLL, & STAT pathways. But how does this epigenetic and transcriptional state behave in vivo? Let's transplant and see! 4/13

We engineered NUP98::NSD1 fusion using CRISPR/Cas9 in human blood stem cells. Fetal-derived cells rapidly became leukemic; postnatal cells less so; pediatric/adult cells showed resistance. Why are fetal cells uniquely vulnerable to leukemia initiation? 3/13

NUP98-rearranged AML in children is aggressive with poor survival. Using human stem cells across fetal, postnatal, pediatric, & adult stages, we found leukemia initiation strongly depends on developmental timing – it's all about WHEN mutations arise. 2/13