Stress hematopoiesis induces a proliferative advantage in TET2 deficiency

Autor: Michelle Moksa, Mira Liebman, Vinothkumar Rajan, Martin Hirst, Rachel Woodside, Marcus Wong, Annaick Carles, Keon Collett, Jason N. Berman, Sergey V. Prykhozhij
Rok vydání: 2021
Předmět:
Zdroj: Leukemia. 36:809-820
ISSN: 1476-5551
0887-6924
Popis: 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.
Databáze: OpenAIRE
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