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.
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The authors would like to thank all members of the animal facility, genomics and flow cytometry core facilities of the University of Ulm, Germany. The work was supported by a grant received by VPSR from the Ministry of Science, Research and the Art (MWK), Baden-Württemberg, Germany (Junior-professor Program). CB was funded by a grant from the DFG (SFB 1074 project A4 to CB). We thank Prof. Konstanze Döhner and Prof. Hartmut Döhner (Department of Internal Medicine III, University Hospital Ulm) for providing patient samples. We thank Marc Young (Institute of Immunology, University Hospital Ulm) for his assistance with generating Fig. 1A.
The authors declare no competing interests.
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Pulikkottil, A.J., Bamezai, S., Ammer, T. et al. TET3 promotes AML growth and epigenetically regulates glucose metabolism and leukemic stem cell associated pathways. Leukemia (2021). https://doi.org/10.1038/s41375-021-01390-3