Graphical Abstract Highlights d SoNar serves as a unique tool for in vitro/in vivo studies of stem cell metabolisms d SoNar-high cells prefer glycolysis and are enriched for leukemia-initiating cells d Leukemia-initiating cells home to endosteal niches and prefer symmetric divisions d PDK2 sustains metabolic and leukemogenic activities of leukemia-initiating cells In Brief Hao et al. reveal that a genetically encoded metabolic sensor, SoNar, precisely monitors the metabolic status of leukemia-initiating cells (LICs) both in vitro and in vivo. LICs prefer homing to endosteal niches and symmetric divisions to maintain their leukemogenic activities. PDK2 fine-tunes the glycolysis and cell-fate determinations of LICs. Hao et al., 2019, Cell Metabolism 29, 950-965 April 2, 2019 ª 2018 Elsevier Inc. SUMMARYThe metabolic properties of leukemia-initiating cells (LICs) in distinct bone marrow niches and their relationships to cell-fate determinations remain largely unknown. Using a metabolic imaging system with a highly responsive genetically encoded metabolic sensor, SoNar, we reveal that SoNar-high cells are more glycolytic, enriched for higher LIC frequency, and develop leukemia much faster than SoNar-low counterparts in an MLL-AF9-induced murine acute myeloid leukemia model. SoNar-high cells mainly home to and locate in the hypoxic endosteal niche and maintain their activities through efficient symmetric division. SoNar can indicate the dynamics of metabolic changes of LICs in the endosteal niche. SoNar-high human leukemia cells or primary samples have enhanced clonogenic capacities in vitro or leukemogenesis in vivo. PDK2 fine-tunes glycolysis, homing, and symmetric division 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.

How metabolic status controls the fates of different types of leukemia cells remains elusive. Using a SoNar-transgenic mouse line, we demonstrated that B cell acute lymphoblastic leukemia (B-ALL) cells had a preference in using oxidative phosphorylation. B-ALL cells with a low SoNar ratio (SoNar-low) had enhanced mitochondrial respiration capacity, mainly resided in the vascular niche, and were enriched with more functional leukemia-initiating cells than that of SoNar-high cells in a murine B-ALL model. The SoNar-low cells were more resistant to cytosine arabinoside (Ara-C) treatment. cyclic adenosine 3′,5′-monophosphate response element–binding protein transactivated pyruvate dehydrogenase complex component X and cytidine deaminase to maintain the oxidative phosphorylation level and Ara-C–induced resistance. SoNar-low human primary B-ALL cells also had a preference for oxidative phosphorylation. Suppressing oxidative phosphorylation with several drugs sufficiently attenuated Ara-C–induced resistance. Our study provides a unique angle for understanding the potential connections between metabolism and B-ALL cell fates.

The connections between energy metabolism and stemness of hematopoietic stem cells (HSCs) at different developmental stages remain largely unknown. We herein generate a transgenic mouse line for the genetically encoded NADH/NAD+ sensor (SoNar) and demonstrate that there exist three distinct fetal liver hematopoietic cell populations according to the ratios of SoNar fluorescence. SoNar-low cells have an enhanced level of mitochondrial respiration, but similar glycolytic level to SoNar-high cells. Interestingly, 10% of SoNar-low cells are enriched for 65% of total immunophenotypical fetal liver HSCs (FL-HSCs) and contain approximately 5-fold greater functional HSCs than that of SoNar-high counterparts. SoNar can monitor sensitively the dynamic changes of energy metabolism in HSCs both in vitro and in vivo. Mechanistically, STAT3 transactivates MDH1 to sustain the malate-aspartate NADH shuttle activity and the HSC self-renewal and differentiation. We reveal an unexpected metabolic program of FL-HSCs and provide a powerful genetic tool for metabolic studies of HSCs or other types of stem cells.