TET3 promotes AML growth and epigenetically regulates glucose metabolism and leukemic stem cell associated pathways.
Leukemia
; 36(2): 416-425, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34462525
ABSTRACT
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+ HSPCs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
/
Leucemia Mieloide Aguda
/
Regulação Leucêmica da Expressão Gênica
/
Epigênese Genética
/
Dioxigenases
/
Glucose
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Leukemia
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Alemanha