Transcriptional contingency in the early hematopoiesis of inherited bone marrow failure syndromes

Abstract

The inherited bone marrow failure syndromes (IBMFS) are a group of heterogeneous genetic diseases caused by germline pathogenic variants in genes involved in hematopoiesis and genomic integrity. Despite sharing common phenotypical manifestations that have aided opportune diagnosis, such as bone marrow failure, congenital malformations and an increased predisposition to develop cancer, little is known about the shared and distinctive transcriptional programs in their hematopoietic stem and progenitor cells compartment that underlie the clinical manifestations of each disease. In this work we have successfully integrated and analyzed the publicly available scRNAseq datasets of HSPCs from patients with Fanconi anemia (FA) and Telomere Biology disorders (TBD), as well as healthy controls. Once integrated, we performed quality control metrics, as well as batch effect correction using different methods. Through dimensionality reduction, cell clustering and cell type annotation we found distinctive gene expression profiles per syndrome and per cell type, as well as orchestrated gene expression profiles, including upregulation of inflammatory pathways and cell proliferation pathways. This work shows the integration of datasets from FA and TBD, two major IBMFS, and provides the basis for an accumulative, comparative, and integrated atlas of scRNAseq data from patients with IBMFS.