Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells

Fatih Kocabas, Junke Zheng, Suwannee Thet, Neal G. Copeland, Nancy A. Jenkins, Ralph J. DeBerardinis, Chengcheng Zhang and Hesham A. Sadek


The role of Meis1 in leukemia is well established, but its role in hematopoietic stem cells (HSCs) remains poorly understood. Previously, we showed that HSCs utilize glycolytic metabolism to meet their energy demands. However, the mechanism of regulation of HSC metabolism, and the importance of maintaining this distinct metabolic phenotype on HSC function has not been determined. More importantly, the primary function of Meis1 in HSCs remains unknown. Here we examined the effect of loss of Meis1 on HSC function and metabolism. Inducible Meis1 deletion in adult mice resulted in apoptosis, loss of HSC quiescence and failure of bone marrow repopulation following transplantation. While we previously showed that Meis1 regulates Hif-1α transcription in vitro, we demonstrate here that loss of Meis1 results in downregulation of both Hif-1α and Hif-2α in HSCs. This resulted in a shift to mitochondrial metabolism, increased reactive oxygen species (ROS) production, and apoptosis of HSCs. Finally, we demonstrate that the effect of Meis1 KO on HSCs is entirely mediated through ROS where treatment of the Meis1 KO mice with the scavenger N-acetylcystein (NAC) restored HSC quiescence and rescued HSC function. These results uncover an important transcriptional network that regulates metabolism, oxidant defense, and maintenance of HSCs.

  • Submitted May 30, 2012.
  • Accepted September 11, 2012.