Dissecting infant leukemia developmental origins with a hemogenic gastruloid model
Current in vitro models of developmental blood formation lack spatio-temporal accuracy and weakly replicate successive waves of hematopoiesis. Herein, we describe a mouse embryonic stem cell (SC)-derived 3D hemogenic gastruloid (haemGx) that captures multi-wave blood formation, progenitor specification from hemogenic endothelium (HE), and generates hematopoietic progenitors capable of short-term engraftment of immunodeficient mice upon maturation in an in vivo niche. We took advantage of the haemGx model to interrogate the origins of infant acute myeloid leukemia (infAML). We focused on MNX1-driven leukemia, representing the commonest genetic abnormality unique to the infant group. Enforced MNX1 expression in haemGx promotes the expansion and in vitro transformation of yolk sac-like erythroid-myeloid progenitors at the HE-to-hematopoietic transition to faithfully recapitulate patient transcriptional signatures. By combining phenotypic, functional, and transcriptional profiling, including at the single-cell level, we establish the haemGx as a useful new model for the study of normal and leukemic embryonic hematopoiesis.
Authors
- G. Ionescu (ORCID: https://orcid.org/0000-0001-5748-4198)
- Gabriel Torregrosa (ORCID: https://orcid.org/0000-0003-4528-5663)
- Mirco Ponzoni (ORCID: https://orcid.org/0000-0002-6164-4286)
- Ylenia Cicirò (ORCID: https://orcid.org/0000-0003-1607-3266)
- Liza Dijkhuis
- Susanne van den Brink (ORCID: https://orcid.org/0000-0003-3683-7737)
- Víctor Hernández-Hernández (ORCID: https://orcid.org/0000-0002-4424-1848)
- Denise Ragusa (ORCID: https://orcid.org/0000-0002-0303-8683)
- Fabio Pastorino (ORCID: https://orcid.org/0000-0002-8312-808X)
- Connor Byrne
- Jordi García‐Ojalvo (ORCID: https://orcid.org/0000-0002-3716-7520)
- Kamil R. Kranc (ORCID: https://orcid.org/0000-0001-7547-4989)
- Ayona Johns
- Alfonso Martínez Arias (ORCID: https://orcid.org/0000-0002-1781-564X)
- Cristina Pina (ORCID: https://orcid.org/0000-0002-2575-6301)
- Anna Bigas (ORCID: https://orcid.org/0000-0003-4801-6899)
- Joana Cerveira (ORCID: https://orcid.org/0000-0002-1910-8586)
- Chun-Wai Suen (ORCID: https://orcid.org/0000-0003-2641-9937)
- Michele Cilli
Institutions
- Queen Mary University of London (GB)
- Universitat Pompeu Fabra (ES)
- University of Cambridge (GB)
- Cancer Institute (WIA) (IN)
- Istituto Giannina Gaslini (IT)
- Sanquin (NL)
- Josep Carreras Leukaemia Research Institute (ES)
- Hospital Del Mar (ES)
- Ospedale Policlinico San Martino (IT)
- Amsterdam University Medical Centers (NL)
- Karl Landsteiner Society (AT)
- Brunel University of London (GB)
- Vrije Universiteit Amsterdam (NL)
Publication Details
- Journal
- eLife
- Published
- 2025-02-03
- DOI
- https://doi.org/10.7554/elife.102324
- Primary Topic
- Zebrafish Biomedical Research Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00