PUBLICATION

Stress hematopoiesis induces a proliferative advantage in TET2 deficiency

Authors
Rajan, V., Collett, K., Woodside, R., Prykhozhij, S.V., Moksa, M., Carles, A., Wong, M., Liebman, M., Hirst, M., Berman, J.N.
ID
ZDB-PUB-211001-3
Date
2021
Source
Leukemia   36(3): 809-820 (Journal)
Registered Authors
Berman, Jason, Prykhozhij, Sergey, Rajan, Vinothkumar, Woodside, Rachel
Keywords
none
MeSH Terms
  • Animals
  • Cell Proliferation
  • Dioxygenases/genetics*
  • Disease Models, Animal
  • Gene Deletion
  • Gene Silencing
  • Hematologic Neoplasms/genetics*
  • Hematopoiesis*
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/metabolism
  • Humans
  • Leukemia, Myeloid, Acute/genetics
  • Loss of Function Mutation
  • Myelodysplastic Syndromes/genetics
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics*
PubMed
34588613 Full text @ Leukemia
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes