TY - JOUR
T1 - The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia
AU - Erdem, Ayşegül
AU - Marin, Silvia
AU - Pereira-Martins, Diego A
AU - Cortés, Roldán
AU - Cunningham, Alan
AU - Pruis, Maurien G
AU - de Boer, Bauke
AU - van den Heuvel, Fiona A J
AU - Geugien, Marjan
AU - Wierenga, Albertus T J
AU - Brouwers-Vos, Annet Z
AU - Rego, Eduardo M
AU - Huls, Gerwin
AU - Cascante, Marta
AU - Schuringa, Jan Jacob
N1 - Funding Information:
This work was supported by a grant from the EU (ITN-EJD HaemMetabolome (H2020-MSCA-ITN-2015 675790) awarded to J.J. Schuringa and to M. Cascante. A.E. and A.C. gratefully acknowledge receipt of a Marie Curie Fellowship and are participants in the same Initial Training Network. S.M., R.C., and M.C. acknowledge also the support of Icrea Academia (ICREA Foundation) and 2017-SGR-1033 (AGAUR, Generalitat de Catalunya). We thank Luise A. Simoes for technical assistance. D.A.P.M. received a fellowship from FAPESP (Grant #2017/23117-1).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Acute myeloid leukemia remains difficult to treat due to strong genetic heterogeneity between and within individual patients. Here, we show that Pyruvate dehydrogenase kinase 1 (PDK1) acts as a targetable determinant of different metabolic states in acute myeloid leukemia (AML). PDK1low AMLs are OXPHOS-driven, are enriched for leukemic granulocyte-monocyte progenitor (L-GMP) signatures, and are associated with FLT3-ITD and NPM1cyt mutations. PDK1high AMLs however are OXPHOSlow, wild type for FLT3 and NPM1, and are enriched for stemness signatures. Metabolic states can even differ between genetically distinct subclones within individual patients. Loss of PDK1 activity releases glycolytic cells into an OXPHOS state associated with increased ROS levels resulting in enhanced apoptosis in leukemic but not in healthy stem/progenitor cells. This coincides with an enhanced dependency on glutamine uptake and reduced proliferation in vitro and in vivo in humanized xenograft mouse models. We show that human leukemias display distinct metabolic states and adaptation mechanisms that can serve as targets for treatment.
AB - Acute myeloid leukemia remains difficult to treat due to strong genetic heterogeneity between and within individual patients. Here, we show that Pyruvate dehydrogenase kinase 1 (PDK1) acts as a targetable determinant of different metabolic states in acute myeloid leukemia (AML). PDK1low AMLs are OXPHOS-driven, are enriched for leukemic granulocyte-monocyte progenitor (L-GMP) signatures, and are associated with FLT3-ITD and NPM1cyt mutations. PDK1high AMLs however are OXPHOSlow, wild type for FLT3 and NPM1, and are enriched for stemness signatures. Metabolic states can even differ between genetically distinct subclones within individual patients. Loss of PDK1 activity releases glycolytic cells into an OXPHOS state associated with increased ROS levels resulting in enhanced apoptosis in leukemic but not in healthy stem/progenitor cells. This coincides with an enhanced dependency on glutamine uptake and reduced proliferation in vitro and in vivo in humanized xenograft mouse models. We show that human leukemias display distinct metabolic states and adaptation mechanisms that can serve as targets for treatment.
U2 - 10.1038/s41467-022-28737-3
DO - 10.1038/s41467-022-28737-3
M3 - Article
C2 - 35232995
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1105
ER -