Metabolic Properties Of Leukemia-initiating Cells And Their Roles In Cell Fate Determinations

Acute myeloid leukemia(AML)is the most prevalent acute leukemia in adults.Leukemia-initiating cells(LICs)are considered to responsible for the development,relapse and chemo-resistance of leukemia.Reprogrammed metabolic alterations may be important for the cell-fate commitments of LICs including self-renewal,homing,differentiation,and apoptosis.However,the metabolic properties of LICs and their roles in cell fate determinations(such as homing and symmetrical division)remain largely unknown.Also,the location of LICs in the bone marrow niches is unclear.Address these questions are important for AML therapy.By using a MLL-AF9-induced murine acute myeloid leukemia model with a highly responsive genetically encoded metabolic sensor,SoNar,we reveal a heterogeneous metabolic status of AML cells.Metabolic imaging and bone marrow transplantations showed that SoNar-high AML cells are more glycolytic and have greater leukemogenic potential than SoNar-low counterparts.Limiting dillutin assay further revealed that SoNar-high AML cells are highly enriched for functional LICs.More importantly,SoNar-high human AML cells or primary samples have enhanced clonogenic capacities in vitro or leukemogenesis in vivo.Moreover,by using an ex vivo and in vivo imaging system we revealed that SoNar-high AML cells mainly home to and locate in the endosteal niche and maintain their activities through efficient symmetric division.By screening a number of genes involved in glucose metabolism,we revealed that PDK2 highly expressed in SoNar-high AML cells.PDK2 deficiency decrease the glycolysis and leukemogenic capacities of LICs,as well as its symmetrical division and homing abilities.Taken together,using a unique metabolic sensor,SoNar,we reveal that SoNar-high cells are highly enriched for LICs,and prefer glycolysis to maintain their homing,locating and symmetric division.PDK2 fine-tunes glycolysis and cell fate determinations of LICs.These findings provide a unique angle for the study of metabolisms in stem cells,and may lead to development of novel strategies for cancer treatment.