[Role of HIF1A in the development of myelodysplastic syndromes]

Myelodysplastic syndromes (MDS), a group of heterogeneous hematopoietic disorders, are characterized by multi-lineage dysplasia and ineffective hematopoiesis. Despite identifying multiple gene mutations in patients with MDS, their main clinical features are similar. To resolve the discrepancy between genotypes and phenotypes, we performed transcriptome and epigenome analyses to ascertain the shared underlying mediator (s) of MDS etiology and identified HIF1A signaling as a central pathobiological mediator of MDS. HIF1A is a critical regulator for several physiological pathways associated with stem-cell maintenance, angiogenesis, glucose-metabolism, and immune activation. We identified dysregulated HIF1A signature in human patients with MDS. Using mouse genetic models, we demonstrated that the dysregulation of HIF1A could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS-driver mutations. The genetic disruption of HIF1A resolves MDS phenotypes. These findings suggest that HIF1A is an effective therapeutic target for a broad spectrum of patients with MDS.