Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies characterized by ineffective hematopoiesis, dysplastic morphology, and risk of progression to acute myeloid leukemia. While genomic alterations intrinsic to malignant MDS disease-initiating cells have been well-characterized, molecular assessment of the bone marrow in situ has been limited. Here we present single cell spatial assessment of gene expression, T cell receptors, as well as MDS-defining mutations and RNA isoforms within fixed, decalcified human bone marrow core biopsies (41 MDS, 15 controls) paired with single cell immunogenomic analysis of bone marrow aspirates (35 MDS, 6 controls). Bone marrow spatial analyses of >7.47×106 cells identified hematopoietic and non-hematopoietic populations not readily captured in dissociated tissue. We developed computational methods to compare ecological niche structures, revealing enriched hematopoietic niches and reorganization of T cell immunity in MDS patient bone marrow. In situ genotyping of mutant cells revealed increased TGFbeta expression in malignant megakaryocytes suppressing local T cell cytotoxicity. By contrast, TGFbeta signaling was disrupted in mutant cells due to aberrant splicing of multiple TGFbeta signaling components. This study provides a spatially resolved landscape of human MDS bone marrow and uncovers mechanisms by which malignant cells simultaneously promote intrinsic clonal persistence while rewiring the microenvironment for immune escape.
Cohesin bridging as a physical principle of enhancer-promoter communication
Central to genome function, enhancers are non-coding sequences that can control transcription from promoters hundreds of kilobases away. Yet the physical basis of this long-range