TET3 promotes AML growth and epigenetically regulates glucose metabolism and leukemic stem cell associated pathways.
Animals
Apoptosis
Cell Proliferation
Dioxygenases
/ genetics
Epigenesis, Genetic
Gene Expression Regulation, Leukemic
Glucose
/ metabolism
Humans
Leukemia, Myeloid, Acute
/ genetics
Mice
Mice, Inbred NOD
Mice, SCID
Neoplastic Stem Cells
/ metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
07
04
2021
accepted:
17
08
2021
revised:
07
08
2021
pubmed:
1
9
2021
medline:
16
2
2022
entrez:
31
8
2021
Statut:
ppublish
Résumé
Acute myeloid leukemia (AML) is considered a poor prognosis malignancy where patients exhibit altered glucose metabolism and stem cell signatures that contribute to AML growth and maintenance. Here, we report that the epigenetic factor, Ten-Eleven Translocation 3 (TET3) dioxygenase is overexpressed in AML patients and functionally validated human leukemic stem cells (LSCs), is required for leukemic growth by virtue of its regulation of glucose metabolism in AML cells. In human AML cells, TET3 maintains 5-hydroxymethylcytosine (5hmC) epigenetic marks and expression of early myeloid progenitor program, critical glucose metabolism and STAT5A signaling pathway genes, which also positively correlate with TET3 expression in AML patients. Consequently, TET3 depletion impedes hexokinase activity and L-Lactate production in AML cells. Conversely, overexpression of TET3 in healthy human hematopoietic stem progenitors (HSPCs) upregulates the expression of glucose metabolism, STAT5A signaling and AML associated genes, and impairs normal HSPC lineage differentiation in vitro. Finally, TET3 depletion renders AML cells highly sensitive to blockage of the TET3 downstream pathways glycolysis and STAT5 signaling via the combination of 2-Deoxy-D-glucose and STAT5 inhibitor which preferentially targets AML cells but spares healthy CD34
Identifiants
pubmed: 34462525
doi: 10.1038/s41375-021-01390-3
pii: 10.1038/s41375-021-01390-3
doi:
Substances chimiques
TET3 protein, human
EC 1.-
Dioxygenases
EC 1.13.11.-
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
416-425Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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