Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis.

The balance between oxidative and nonoxidative glucose metabolism is essential for a number of pathophysiological processes. By deleting enzymes that affect aerobic glycolysis with different potencies, we examine how modulating glucose metabolism specifically affects hematopoietic and leukemic cell populations. We find that a deficiency in the M2 pyruvate kinase isoform (PKM2) reduces the levels of metabolic intermediates important for biosynthesis and impairs progenitor function without perturbing hematopoietic stem cells (HSCs), whereas lactate dehydrogenase A (LDHA) deletion significantly inhibits the function of both HSCs and progenitors during hematopoiesis. In contrast, leukemia initiation by transforming alleles putatively affecting either HSCs or progenitors is inhibited in the absence of either PKM2 or LDHA, indicating that the cell-state-specific responses to metabolic manipulation in hematopoiesis do not apply to the setting of leukemia. This finding suggests that fine-tuning the level of glycolysis may be explored therapeutically for treating leukemia while preserving HSC function.

Haematopoietic stem cells depend on Galpha(s)-mediated signalling to engraft bone marrow.

Haematopoietic stem and progenitor cells (HSPCs) change location during development and circulate in mammals throughout life, moving into and out of the bloodstream to engage bone marrow niches in sequential steps of homing, engraftment and retention. Here we show that HSPC engraftment of bone marrow in fetal development is dependent on the guanine-nucleotide-binding protein stimulatory alpha subunit (Galpha(s)). HSPCs from adult mice deficient in Galpha(s) (Galpha(s)(-/-)) differentiate and undergo chemotaxis, but also do not home to or engraft in the bone marrow in adult mice and demonstrate a marked inability to engage the marrow microvasculature. If deleted after engraftment, Galpha(s) deficiency did not lead to lack of retention in the marrow, rather cytokine-induced mobilization into the blood was impaired. Testing whether activation of Galpha(s) affects HSPCs, pharmacological activators enhanced homing and engraftment in vivo. Galpha(s) governs specific aspects of HSPC localization under physiological conditions in vivo and may be pharmacologically targeted to improve transplantation efficiency.

Vitamin D receptor deletion leads to increased hematopoietic stem and progenitor cells residing in the spleen.

Bone components participate in the regulation of hematopoietic stem cells in the adult mammal. Vitamin D regulates bone mineralization and is associated with pleiotropic effects in many cell types, including putative roles in hematopoietic differentiation. We report that deletion of the vitamin D receptor (VDR) in hematopoietic cells did not result in cell autonomous perturbation of hematopoietic stem cell or progenitor function. However, deletion of VDR in the microenvironment resulted in a marked accumulation of hematopoietic stem cells in the spleen that could be reversed by calcium dietary supplementation. These data suggest that VDR participates in restricting splenic hematopoiesis through maintenance of bone calcium homeostasis and are consistent with the concept that calcium regulation through VDR is a central participant in localizing adult hematopoiesis preferentially to bone marrow.