Dissecting infant leukemia developmental origins with a hemogenic gastruloid model
Year: 2025
Type: preprint
Abstract: 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.
Source: eLife
DOI: 10.7554/elife.102324
Authors: Denise Ragusa, Chun Wai Suen, Gabriel Torregrosa Cortes, Fabio Pastorino, Ayona Johns, Ylenia Cicirò, Liza Dijkhuis, Susanne van den Brink, Michele Cilli, Connor Byrne, Giulia-Andreea Ionescu, Joana Cerveira, Kamil R Kranc, Victor Hernandez-Hernandez, Mirco Ponzoni, Anna Bigas, Jordi Garcia-Ojalvo, Alfonso Martínez Arias, Cristina Pina
Institutions: Brunel University of London, University of Cambridge, Universitat Pompeu Fabra, Istituto Giannina Gaslini, Josep Carreras Leukaemia Research Institute, Hospital Del Mar, Hospital del Mar Research Institute, Centro de Investigación Biomédica en Red de Cáncer, Ospedale Policlinico San Martino, Institute of Cancer Research, Queen Mary University of London, Institute of Cancer Research, Barts Cancer Institute, Sanquin, Amsterdam UMC Location Vrije Universiteit Amsterdam
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: European Molecular Biology Organization, Brunel University London, Wellcome Trust, Leuka, Royal Society of Biology, Kay Kendall Leukaemia Fund, National Centre for the Replacement, Refinement and Reduction of Animals in Research, Human Frontier Science Program, Generalitat de Catalunya, Ministero della Salute, Lady Tata Memorial Trust, Ministerio de Ciencia e Innovación, National Centre for the Replacement Refinement and Reduction of Animals in Research, Little Princess Trust, European Research Council, Agencia Estatal de Investigación, Ministerio de Universidades
OpenAlex ID: W4407108721