GLUCOCORTICOID-INDUCED LEUCINE ZIPPER (GILZ) INTRINSICALLY REGULATES HEMATOPOIETIC STEM CELL FUNCTION

The maintenance of hematopoietic stem cells (HSC) is linked to their quiescent state, while HSC proliferation is associated with differentiation and a loss of long-term stem cell potential. The balance between HSC quiescence and proliferation is tightly regulated by intrinsic and extrinsic cues in the bone marrow. Endogenous glucocorticoid hormones (GC) regulate HSC homing via control of CXCR4 expression. Glucocorticoid- Induced Leucine Zipper (GILZ) is a gene rapidly induced by GC. It mediates many of GC’ anti-proliferative and anti-inflammatory effects in several cell types. We found that GILZ is expressed in HSC and addressed its role in hematopoiesis using GILZ knock-out (KO) mice. At steady state, young GILZ-KO mice did not show alteration in HSC number and lineage commitment compared to WT mice. However, com- petitive transplantation studies revealed a significant decrease in the fre- quency and number of GILZ-KO compared to WT HSC, suggesting that GILZ-deficient HSC have competitive disadvantage compared to WT cells. RNAseq analysis of gene expression revealed several deregulated cellular pathways implicated in HSC function in GILZ KO compared to WT HSC. Importantly, Gene Set Enrichment Analysis showed a signifi- cant depletion of the HSC signature and an enrichment in the mTOR signalling signature in GILZ deficient HSC. Consistently, GILZ deficient HSC showed enhanced proliferation as revealed by flow cytomery analy- sis of Ki67 expression and DNA content. Mice transplanted with GILZ deficient cells showed significantly earlier mortality compared to WT cells-transplanted mice in 5-FU treatment experiments, demonstrating a cell-intrinsic role of GILZ in HSC function. Overall, these data identify GILZ is a novel regulator of HSCs function.