Single-cell RNA sequencing of a new transgenic t(8;21) preleukemia mouse model reveals regulatory networks promoting leukemic transformation.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
14 Oct 2023
14 Oct 2023
Historique:
received:
24
04
2023
accepted:
05
10
2023
revised:
22
09
2023
medline:
15
10
2023
pubmed:
15
10
2023
entrez:
14
10
2023
Statut:
aheadofprint
Résumé
T(8;21)(q22;q22), which generates the AML1-ETO fusion oncoprotein, is a common chromosomal abnormality in acute myeloid leukemia (AML) patients. Despite having favorable prognosis, 40% of patients will relapse, highlighting the need for innovative models and application of the newest technologies to study t(8;21) leukemogenesis. Currently, available AML1-ETO mouse models have limited utility for studying the pre-leukemic stage because AML1-ETO produces mild hematopoietic phenotypes and no leukemic transformation. Conversely, overexpression of a truncated variant, AML1-ETO9a (AE9a), promotes fully penetrant leukemia and is too potent for studying pre-leukemic changes. To overcome these limitations, we devised a germline-transmitted Rosa26 locus AE9a knock-in mouse model that moderately overexpressed AE9a and developed leukemia with long latency and low penetrance. We observed pre-leukemic alterations in AE9a mice, including skewing of progenitors towards granulocyte/monocyte lineages and replating of stem and progenitor cells. Next, we performed single-cell RNA sequencing to identify specific cell populations that contribute to these pre-leukemic phenotypes. We discovered a subset of common myeloid progenitors that have heightened granulocyte/monocyte bias in AE9a mice. We also observed dysregulation of key hematopoietic transcription factor target gene networks, blocking cellular differentiation. Finally, we identified Sox4 activation as a potential contributor to stem cell self-renewal during the pre-leukemic stage.
Identifiants
pubmed: 37838757
doi: 10.1038/s41375-023-02063-z
pii: 10.1038/s41375-023-02063-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA104509
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : P30CA23100
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : T32CA009523
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : T32CA009523
Informations de copyright
© 2023. The Author(s).
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