Abstract
The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1-regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, (2) repressed by PML-RARA, and (3) functionally involved in neutrophil differentiation and cell viability of APL cells.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Anthracyclines / pharmacology
-
Anthracyclines / therapeutic use
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use
-
Cell Differentiation / drug effects
-
Cell Differentiation / genetics*
-
Cell Survival / drug effects
-
Cell Survival / genetics
-
Cells, Cultured
-
Gene Expression Regulation, Enzymologic / drug effects
-
Gene Expression Regulation, Enzymologic / physiology
-
Gene Expression Regulation, Leukemic / drug effects
-
Gene Expression Regulation, Leukemic / physiology
-
Glycolysis / genetics
-
Hexokinase / genetics
-
Hexokinase / metabolism
-
Hexokinase / physiology*
-
Humans
-
Leukemia, Promyelocytic, Acute / drug therapy
-
Leukemia, Promyelocytic, Acute / genetics
-
Leukemia, Promyelocytic, Acute / pathology*
-
Neutrophils / drug effects
-
Neutrophils / metabolism
-
Neutrophils / pathology
-
Neutrophils / physiology*
-
Oncogene Proteins, Fusion / genetics
-
Oncogene Proteins, Fusion / metabolism
-
Oncogene Proteins, Fusion / physiology
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins / physiology*
-
Trans-Activators / genetics
-
Trans-Activators / metabolism
-
Trans-Activators / physiology*
-
Tretinoin / pharmacology
-
Tretinoin / therapeutic use
Substances
-
Anthracyclines
-
Antineoplastic Agents
-
Oncogene Proteins, Fusion
-
Proto-Oncogene Proteins
-
Trans-Activators
-
promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
-
proto-oncogene protein Spi-1
-
Tretinoin
-
Hexokinase