3093 – MODELLING MNX1-OVEREXPRESSION IN A GASTRULOID MODEL OF EMBRYONIC HAEMATOPOIESIS IDENTIFIES A CANDIDATE CELL OF ORIGIN FOR T(7;12) AML

• Published in: Experimental hematology 2024-08, Vol.137, p.104415, Article 104415
• Main Authors: Johns, Ayona, Cicirò, Ylenia, Byrne, Connor Connor, Dijkhuis, Liza, Ionescu, Giulia-Andreea, Pina, Cristina, Ragusa, Denise, Suen, Chun Wai
• Format: Article
• Language: English
• ISSN: 0301-472X
• DOI: 10.1016/j.exphem.2024.104415

Infant Acute Myeloid Leukemia (infAML) is a lethal disease with unique mutations hard to model in non-fetal cells, as they may selectively transform embryonic progenitors and/or depend on embryonic hemopoietic niches. Translocation t(7;12) is unique to infAML leading to MNX1-overexpression (oe). We engineered t(7;12) in vitro with partial recapitulation of MNX1-AML signatures. Others showed that MNX1-oe transforms mouse fetal liver cells to generate a transplantable AML. But, recapitulation of t(7;12)-transcriptome remains incomplete, and the cell-of-origin (CoO) elusive. We recently established a 3D model of hemogenic development using self-organising ES cell gastruloids that recapitulate early development with spatial and temporal coherence. Hemogenic gastruloids (hGx) recapitulate sequential waves of yolk sac (YS)-like and aorta-gonad-mesonephros (AGM)-like blood specification from hemogenic endothelium (HE) and also generate niche cells. We thus sought to interrogate the effect of MNX1-oe on blood development in hGx to identify an MNX1-AML CoO. MNX1-oe triggered time-dependent expansion of Kit+ cells at the emergence of YS erythoid-myeloid progenitors from HE. HGx Kit+ cells were transformed through serial colony replating and their transcriptomes captured t(7;12) AML signatures. Combined molecular and cellular analyses of MNX1-oe through hGx development showed more limited MNX1-oe effects in later-emerging AGM-like progenitors, placing MNX1 CoO within YS hemopoiesis. Altogether, our results pinpoint the developmental origin of MNX1-AML, explaining the infant timing of the disease and the failure to recapitulate it in post-natal cells. We suggest that hGx can be used to identify the CoO of other infAML. The throughput multi-well nature of hGx cultures makes them amenable to drug screening for potential discovery of targeted therapies against these lethal diseases.