Deletion of mouseSetd4promotes the recovery of hematopoietic failure

Abstract

AbstractAcquired hematopoietic failure is commonly caused by therapeutic and accidental exposure to toxic agents to the bone marrow (BM). Efficient recovery from the BM failure is not only dictated by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells, but also nourished by the BM environment niche. Identification of genetic factors that improve the recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized, putative non-histone methyl-transferase whose physiological substrates have not yet been fully identified. By inducingSetd4deletion in adult mice, we found that loss ofSetd4improved the survival of whole body irradiation induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSC), and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to a radiation resistance of theSetd4deficient HSC, but thatSetd4deficient HSC were actually more sensitive to radiation. However, theSetd4deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was an enhanced splenic erythropoiesis inSetd4deficient mice. These findings not only revealed a previously unrecognized role of theSetd4as a unique modulator of hematopoiesis, but also underscored the critical role of the BM niche in the recovery of hematopoietic failure. These studies also implicatedSetd4as a potential target for therapeutic inhibition to improve the conditioning of the BM niche prior to allogeneic transplantation.Key pointsDeletion ofSetd4in adult mice improved the survival from hematopoietic failure.Setd4deficiency sensitized HSCs to radiation, but improved bone marrow environment niche.The study suggests that SETD4 as a potential inhibitory target to improve bone marrow niche function for recovery of bone marrow failure.