Transcriptome analysis of circulating lymphoid progenitors after allogeneic stem cell transplantation in humans reveals profound alterations of cellular metabolism (TRAN1P.930)

Abstract

Abstract T-cell reconstitution is delayed by acute Graft-Versus-Host Disease (aGVHD) during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we analyzed transcriptional programs of cell-sorted circulating lymphoid progenitors and CD34+Lin-CD10- non lymphoid progenitors in 12 allo-HSCT patients having (n=4) or not developed (n=8) grade 2 aGVHD and in 4 age-matched healthy donors. Gene expression was quantified on the GeneChip HG u133 plus 2.0. Pathway analyses were performed with KEGG, GSEA and DAVID. Major deregulated pathways included protein synthesis, energy production, cell cycle regulation and response to stress. Notably, Genes from ribosome protein biogenesis, translation machinery (EEF1D, EEF1G, EIF3K) and cell cycle (CCND1, CDK6) were over-expressed in progenitors from patients without aGVHD compared with those from patients affected by aGVHD and from healthy donors. Expressions of genes from the oxidative phosphorylation metabolic pathway (NDUFS2, SDHA, ATP5A1) and genes involved in stress resistance (BTG2, MGST3, HPX) were specifically increased in CD34+Lin-CD10+CD24- lymphoid progenitors from patients without aGVHD. In all, we show that circulating lymphoid T-cell progenitors undergo profound changes in metabolism favoring energy production and response to stress after allo-HSCT in humans. These mechanisms are abolished in case of aGVHD, indicating a persistent cell-intrinsic defect in addition to the impact of aGVHD on the bone marrow environment.