Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single cell resolution

Abstract

ABSTRACTBackgroundEarly hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate and are primed toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we evaluated human HSPCs obtained from young and elderly healthy donors using single-cell RNA sequencing to identify the transcriptional and regulatory perturbations associated with healthy aging at single cell resolution. We then applied this knowledge to identify specific changes associated with the development of myeloid malignancies.ResultsBased on the transcriptional profile obtained, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain age-associated aberrant hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks and detected regulons that were specifically active in elderly individuals. Using the previous findings as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome and acute myeloid leukemia and detected an alteration of the expression dynamics of genes involved in erythroid differentiation and identified specific transcription factors deregulated in acute myeloid leukemia.ConclusionsWe demonstrate that the combination of single cell technologies and computational tools enables the study of a variety of cellular mechanisms involved in early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients.