Please use this identifier to cite or link to this item:
http://bura.brunel.ac.uk/handle/2438/27832
Title: | Dissecting infant leukemia developmental origins with a hemogenic gastruloid model |
Authors: | Ragusa, D Suen, C-W Torregrosa Cortes, G Dijkhuis, L Byrne, C Ionescu, G-A Cerveira, J Kranc, KR Bigas, A Garcia-Ojalvo, J Martinez Arias, A Pina, C |
Keywords: | hematopoiesis;developmental hematopoiesis;leukemia;Infant leukemia;acute myeloid leukemia;MNX1;t(7;12);gastruloid;organoid;single-cell RNA-sequencing |
Issue Date: | 7-Oct-2022 |
Publisher: | Cold Spring Harbor Laboratory |
Citation: | Ragusa, D. et al. (2022) 'Dissecting infant leukemia developmental origins with a hemogenic gastruloid model', bioRxiv, [preprint]. 2022.10.07.511362, pp. 1 - 43. doi: 10.1101/2022.10.07.511362. |
Abstract: | Current in vitro models of developmental blood formation lack spatiotemporal coherence and weakly replicate the hematopoietic microenvironment. Developmentally-appropriate models can enhance understanding of infant acute myeloid leukemia (infAML), which putatively originates in utero and has 50% age-unique genetic events, suggesting unique biology. The commonest genetic abnormality unique to infants involves homeobox gene MNX1, whose leukemogenic mechanisms remain unknown. Recently, 3D self-organising embryonic stem cell (SC)-based gastruloids have shown promise in recapitulating embryonic events with time/space precision. Herein, we report a hemogenic gastruloid (haemGx) system that captures multi-wave blood formation, progenitor specification from hemogenic endothelium (HE), and approximates generation of hematopoietic SC precursors. Enforced MNX1 expression in haemGx promotes HE formation, perturbs endothelial-to-hemogenic transition, and critically achieves transformation, generating myeloid colonies which display MNX1 AML signatures. By combining functional assays with single-cell transcriptomics, we establish the haemGx as a new model of normal and leukemic embryonic hematopoiesis amenable to mechanistic exploration. |
Description: | This article is a preprint and has not been certified by peer review. Data availability: Raw data as well as processed count matrices and post-processed files from single-cell RNA-seq for the time-resolved data is available at E-MTAB-12148. Single-cell RNA-seq for the MNX1 overexpression experiment is available at Array Express with accession code E-MTAB-12149. Bulk RNA-seq of MNX1 overexpressing gastruloids is available at Array Express with accession code E-MTAB-12173. The post-processing was performed in Python on DockerHub: dsblab/single_cell_analysis:0.5. Scripts are available in https://github.com/dsb-lab/blood_gastruloids and Zenodo (https://doi.org/10.5281/zenodo.7053423). The results published here are partly based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) (https://ocg.cancer.gov/programs/target) initiative, of the Acute Myeloid Leukemia (AML) cohort GDC TARGET-AML. The data used for this analysis are available at https://portal.gdc.cancer.gov/projects and https://xenabrowser.net/. |
URI: | https://bura.brunel.ac.uk/handle/2438/27832 |
DOI: | https://doi.org/10.1101/2022.10.07.511362 |
Other Identifiers: | ORCID iD: Cristina Pina https://orcid.org/0000-0002-2575-6301 |
Appears in Collections: | Dept of Life Sciences Research Papers |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
FullText.pdf | Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. | 12.35 MB | Adobe PDF | View/Open |
This item is licensed under a Creative Commons License