Hematopoietic stem cells (HSCs) synthesize less protein per hour, on average, than other hematopoietic progenitors. Limited protein synthesis appears to be a widely shared feature of adult stem cells. The low rate of protein synthesis is necessary for HSC maintenance as genetic changes that modestly increase or decrease protein synthesis each impair HSC function. However, the mechanisms that suppress protein synthesis in adult stem cells remain unexplored. We assessed a number of potential mechanisms and found that the reduced rate of protein synthesis in HSCs as compared to other hematopoietic progenitors is not explained by differences in proteasome activity, cell division rate, or mRNA content. However, adult bone marrow HSCs had increased amounts of hypophosphorylated eukaryotic initiation factor 4E binding protein1 (eIF4E-BP1) and eIF4E-BP2 as compared to other hematopoietic progenitors. Since unphosphorylated eIF4E-BP negatively regulates protein synthesis, this raised the possibility that eIF4E-BPs hypophosphorylation suppresses protein synthesis in HSCs. Consistent with this, genetic inactivation of eIF4E-BP1 and eIF4E-BP2 increased protein synthesis in HSCs and impaired their reconstituting activity. These findings provide insight into the mechanisms that promote adult tissue regenerative capacity by attenuating protein synthesis in stem cells.

Citation Format: Robert A. J. Signer, Le Qi, Sean J. Morrison. Low rates of protein synthesis in hematopoietic stem cells are determined partly by relatively high levels of hypophosphorylated eIF4E-BP. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA12.