Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress

Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Blood (Impact Factor: 10.43). 10/2012; 120(25). DOI: 10.1182/blood-2012-06-435800
Source: PubMed

ABSTRACT The transcription factor Meis1 is preferentially expressed in hematopoietic stem cells (HSCs) and over-expressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. Using inducible knock-out mice, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over long term while steady-state hematopoiesis was sustained in the absence of Meis1. Bone marrow cells of Meis1 deficient mice showed reduced colony formation, contained significantly fewer numbers of long- term HSCs and these Meis1-deficient HSCs exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species (ROS) in HSCs and decreased expression of genes implicated in hypoxia response. Finally, ROS scavenging by N-acetyl cysteine or stabilization of hypoxia-signaling by knockdown of the VHL protein led to reversal of the effects of Meis1-deletion. Taken together, these results demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism.

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    • "This resulted in increases in HSC ROS production, cell cycle entry and proliferation , and apoptosis and decreases in the ability of HSCs to reconstitute the hematopoietic system during serial BM transplantation and to tolerate stress such as 5-fluorouracil administration. These HSC defects could be attenuated by treatment of the knockout mice with NAC, knockdown of VHL, or conditional monoallelic knockout of VHL (Kocabas et al., 2012; Simsek et al., 2010; Takubo et al., 2010; Unnisa et al., 2012). However, overactivation of HIF-1 in HSCs induced by conditional biallelic knockout of VHL or inhibition of PHD is detrimental to HSCs and can lead to HSC premature exhaustion (Eliasson et al., 2010; Takubo et al., 2010). "
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