JARID2 inhibition reprograms human hematopoietic progenitor cells to enhance bone marrow transplantation

Abstract Hematopoietic stem cell (HSC) transplantation is a common treatment for many blood disorders and can be a lifesaving therapy for patients with leukemias, lymphomas, and multiple myeloma. Umbilical cord blood (UCB) serves as a valuable source of hematopoietic stem and progenitor cells (HSPCs) for transplantation, particularly for patients lacking a matched donor. However, the limited number of repopulating cells in UCB units restricts its clinical utility. Our prior studies showed that the genetic deletion of the polycomb repressive complex 2 (PRC2) cofactor Jarid2 in mouse multipotent progenitors (MPPs) conveyed ectopic self-renewal capacity. Here, we hypothesized that the function of human HSPCs could be enhanced through JARID2 inhibition. In this study, we demonstrate that both constitutive and transient knockdown (KD) of JARID2 increases the number and enhances the functionality of human HSPCs both in vitro and in vivo. This phenotype was distinct from the inhibition of EZH2 in UCB cells, suggesting that the mechanism was independent of the PRC2 cofactor activity of JARID2. Mechanistically, JARID2 KD promotes a quiescent, long-term self-renewal gene expression program governed by STAT1 upregulation and characterized by an MHC class II immunophenotype. Analogous to mice, these mechanisms conferred HSC-like potential to human MPPs in vivo. Taken together, these findings highlight JARID2 inhibition as a novel and reversible approach to expand functional UCB-derived HSPCs ex vivo, potentially improving access to stem cell transplantation for a wider patient population.