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DC Field | Value | Language |
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dc.contributor.author | Ragusa, D | - |
dc.contributor.author | Suen, C-W | - |
dc.contributor.author | Torregrosa Cortes, G | - |
dc.contributor.author | Dijkhuis, L | - |
dc.contributor.author | Byrne, C | - |
dc.contributor.author | Ionescu, G-A | - |
dc.contributor.author | Cerveira, J | - |
dc.contributor.author | Kranc, KR | - |
dc.contributor.author | Bigas, A | - |
dc.contributor.author | Garcia-Ojalvo, J | - |
dc.contributor.author | Martinez Arias, A | - |
dc.contributor.author | Pina, C | - |
dc.date.accessioned | 2023-12-10T11:02:25Z | - |
dc.date.available | 2023-12-10T11:02:25Z | - |
dc.date.issued | 2022-10-07 | - |
dc.identifier | ORCID iD: Cristina Pina https://orcid.org/0000-0002-2575-6301 | - |
dc.identifier.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. | en_US |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/27832 | - |
dc.description | This article is a preprint and has not been certified by peer review. | en_US |
dc.description | 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/. | - |
dc.description.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. | en_US |
dc.description.sponsorship | This project was funded by a start-up grant and a BRIEF award from Brunel University London to CP, and by ERC Advanced Grant (MiniEmbryoBlueprint 834580) to AMA. GTC was funded by grant FPU18/05091 from the Spanish Ministry of Universities. CP was also funded by a KKLF Intermediate Fellowship (KL888), a Leuka John Goldman Fellowship for Future Science (2017-2019), and a Wellcome Trust / ISSF Bridge Funding award at the University of Cambridge (2019). JGO acknowledges financial support from the Spanish Ministry of Science and Innovation and FEDER (grant PGC2018-101251-B-I00), by the Maria de Maeztu Programme for Units of Excellence in R&D (grant CEX2018-000792-M), and by the Generalitat de Catalunya (ICREA Academia programme). | en_US |
dc.format.extent | 1 - 43 | - |
dc.format.medium | Electronic | - |
dc.language.iso | en_US | en_US |
dc.publisher | Cold Spring Harbor Laboratory | en_US |
dc.rights | 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. | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | - |
dc.subject | hematopoiesis | - |
dc.subject | developmental hematopoiesis | - |
dc.subject | leukemia | - |
dc.subject | Infant leukemia | - |
dc.subject | acute myeloid leukemia | - |
dc.subject | MNX1 | - |
dc.subject | t(7;12) | - |
dc.subject | gastruloid | - |
dc.subject | organoid | - |
dc.subject | single-cell RNA-sequencing | - |
dc.title | Dissecting infant leukemia developmental origins with a hemogenic gastruloid model | en_US |
dc.type | Article | en_US |
dc.identifier.doi | https://doi.org/10.1101/2022.10.07.511362 | - |
dc.relation.isPartOf | biorXiv | - |
pubs.publication-status | Published online | - |
dc.identifier.eissn | 2692-8205 | - |
dc.rights.holder | The author/funder | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
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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 |
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