Stress hematopoiesis induces a proliferative advantage in TET2 deficiency.
Animals
Cell Proliferation
Dioxygenases
/ genetics
Disease Models, Animal
Gene Deletion
Gene Silencing
Hematologic Neoplasms
/ genetics
Hematopoiesis
Hematopoietic Stem Cells
/ cytology
Humans
Leukemia, Myeloid, Acute
/ genetics
Loss of Function Mutation
Myelodysplastic Syndromes
/ genetics
Zebrafish
/ genetics
Zebrafish Proteins
/ genetics
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
27
12
2020
accepted:
14
09
2021
revised:
02
09
2021
pubmed:
1
10
2021
medline:
12
3
2022
entrez:
30
9
2021
Statut:
ppublish
Résumé
TET2 loss-of-function mutations are recurrent events in a wide range of hematological malignancies and a physiologic occurrence in blood cells of healthy older adults. It is currently unknown what determines if a person harboring a somatic TET2 mutation will progress to myelodysplastic syndrome or acute myeloid leukemia. Here we develop a zebrafish tet2 mutant through which we show that tet2 loss leads to restricted hematopoietic differentiation combined with a modest upregulation of p53, which is also characteristic of many inherited bone marrow failure syndromes. Uniquely in the context of emergency hematopoiesis by external stimuli, such as infection or cytokine stimulation, lack of tet2 leads hematopoietic stem cells to undergo excessive proliferation, resulting in an accumulation of immature cells, which are poised to become leukemogenic following additional genetic/epigenetic perturbations. This same phenomenon observed in zebrafish extends to human hematopoietic stem cells, identifying TET2 as a critical relay switch in the context of stress hematopoiesis.
Identifiants
pubmed: 34588613
doi: 10.1038/s41375-021-01427-7
pii: 10.1038/s41375-021-01427-7
doi:
Substances chimiques
Zebrafish Proteins
0
TET2 protein, zebrafish
EC 1.-
Dioxygenases
EC 1.13.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
809-820Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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