Loss of transfer RNA U34 modifying enzymes impairs hematopoietic stem and progenitor cell differentiation and function

Hematopoietic stem and progenitor cells (HSPCs) require fine-tuned protein translation for their normal maintenance and function. Conserved modifications of the wobble uridine base (U34) in transfer RNAs catalyzed by the Elongator complex are required for optimal protein translation efficacy and fidelity, but their biological importance in mammalian stem and progenitor cells remains largely unexplored. Here, we studied the impact of loss of activity of the catalytic subunit Elp3 of Elongator on HSPC differentiation and function. Hematopoietic-cell-specific depletion of Elp3 in conditional knockout mice resulted in shortened lifespan associated with hematopoietic failure and lymphoma development. Elp3 deletion caused apoptosis of specific bone marrow multipotent progenitors and blocked differentiation of committed progenitors, resulting in blood and bone marrow pancytopenia. In contrast, Elp3-deficient hematopoietic stem cells (HSCs) expanded with age and did not exhaust throughout life, although they were defective in reconstituting hematopoiesis in competitive transplantation assays. Mechanistically, loss of Elp3 did not result in detectable alterations in global protein synthesis rates in any HSPC subset. Rather, Elp3-deficient HSPCs displayed enhanced activity of the stress integrator and apoptosis and cell cycle regulator p53. Thus, this study supports the notion that Elongator activity is required in distinct HSPC subsets to avoid aberrant p53 activation, which otherwise results in discrete loss of function phenotypes in HSCs and downstream progenitors.