Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still,... Show moreTransplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-gamma or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies. Show less
This thesis spans several years of work dedicated to understanding fish genomes. In the first chapter it describes the genome of the first fish for which the entire genome was sequenced through a... Show moreThis thesis spans several years of work dedicated to understanding fish genomes. In the first chapter it describes the genome of the first fish for which the entire genome was sequenced through a large-scale international project, Fugu rubripes. the pufferfish. In particular, it highlights how this fish has a genome that contains as many genes as the human genome, although it is ten times smaller. It also shows that the majority of genes that are found in the human genome can be found in this fish genome as well. In the second chapter we compared fish genomes to the human genome to find regions that have been preserved during evolution and which are therefore likely to have a function, even though they are not genes. We showed that indeed they are functional, and they help to regulate other genes. Knowing all the genes in the genome we could then interrogate how they are expressed, i.e. if they are switched __on__ or __off__ and in particular in chapter 4 we looked at how a specific gene is in charge of gradually switching off genes that are inherited from the mother in a newborn fish embryo. Finally in the last chapter since genome sequencing is now becoming much cheaper and simpler to achieve we set out to map the genome of the common carp and we discuss the best approaches and strategies to obtain a good genome sequence for this species. The common carp is a candidate model system for high-troughput screening. Show less
