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TET3 promotes AML growth and epigenetically regulates glucose metabolism and leukemic stem cell associated pathways


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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Fig. 1: TET3 is aberrantly expressed in AML patients and AML-LSCs.
Fig. 2: TET3 depletion suppress AML cells growth in vitro and in vivo.
Fig. 3: TET3 overexpression augments the AML cell growth and in healthy human HSPCs perturbs myeloid differentiation.
Fig. 4: TET3 regulates the expression of genes associated with glucose metabolism, STAT5A signaling and LSC function.
Fig. 5: Higher TET3 level regulates expression of genes involved in glucose metabolism, STAT5 pathway and LSC function via 5hmC epigenetic marks.
Fig. 6: TET3 depleted AML cells are vulnerable to glucose deprivation.
Fig. 7: TET3 depleted AML cells are very sensitive to chemical inhibitors targeting TET3 downstream genes HK2 and STAT5A.


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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.

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VPSR designed the project, CB discussed and edited the design of the project. AJP, SB, TA and FM performed experiments. AJP, KF and TM performed transplantations. AJP, SB, CB, and VPSR analyzed the data. SB and AJP performed the RNA-seq, ChIP-seq data analysis in collaboration with AS. UK and LQM performed histopathology. NMV contributed research material. AJP, SB, VPSR, and CB contributed to interpretation of patient data. SB, AJP, CB, and VPSR wrote the manuscript.

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Correspondence to Christian Buske or Vijay P. S. Rawat.

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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).

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