Type: Oral
Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: New Insights into The Biology of Myeloproliferative Syndromes
Hematology Disease Topics & Pathways:
Research, Translational Research, Diseases, Myeloid Malignancies
Method: We developed a workflow for generating high-quality spatially resolved data from human archival formalin-fixed paraffin-embedded bone marrow trephine (BMT) material. We perform Xenium analysis on a large (n = 30) cohort of patients with MPN (n = 11 MF, n = 3 PrePMF, n = 8 ET, n = 3 PV, and n = 5 normal BMTs). We integrate the ST output with H&E morphology, demonstrating how this supports cellular segmentation and regional annotation. We develop a graph neural network (GNN) pipeline to facilitate the application of a machine learning model to our ST data.
Results: We identify a total of 6,304,337 BM cells from BMTs from 30 patients, including lymphocyte (CD4+ and CD8+), erythroid, megakaryocyte, endothelial, antigen presenting cell (dendritic cells, monocytes and macrophages), granulocyte, and haematopoietic stem and progenitor cell (HSPC) groups. We identify distinct mesenchymal stromal cell (MSC) groups including osteogenic-MSC and osteoblasts enriched within the endosteal niche, and an adipocytic MSC group enriched within intertrabecular regions. We systematically characterise the endosteal, peritrabecular and intertrabecular microenvironments. We identify and map HSPC and progenitor populations, defining microenvironmental perturbation characteristic of MPN. We quantitively describe the cellular composition of the human marrow, demonstrating how whole-trephine cellular abundance distinguishes both MF and PrePMF patients from those with non-fibrotic MPN (ET and PV) and normal marrows. We find that erythroid and megakaryocyte groups are expanded with increased cell-cell adjacency in MF, potentially reflecting megakaryocyte bias of the shared precursor. Differential expression analysis identifies upregulation of extracellular matrix (ECM)-associated transcripts across nearly all lineages in MF and PrePMF versus the normal marrow, but not in non-fibrotic MPN. Finally, we apply a graph neural network (GNN) approach to our spatially resolved ST-BMT dataset, generating a model which can with high confidence distinguish MPN from normal marrow. This approach furthermore allows high-resolution characterisation of the cellular microenvironmental and spatial features which define MPN.
Conclusions: We present the first whole-section spatial atlas of the human marrow at single cell resolution, demonstrating how ST approaches can provide novel insights into both normal marrow homeostasis and mechanisms underpinning disease progression in MPN. We also demonstrate the opportunities afforded by spatially-resolved single cell data for generating AI-based models with potential for genuine translational applicability, supporting early and accurate diagnosis and prognostication.
Disclosures: Psaila: Blueprint Medicines: Consultancy; Incyte: Consultancy, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Oxford: Patents & Royalties: 2203947.3; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Alethiomics: Consultancy, Current equity holder in private company, Research Funding. Mead: Ionis: Consultancy, Honoraria; Medscape: Honoraria; Karyopharm: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Research Funding; Alethiomics: Consultancy, Current equity holder in private company, Current holder of stock options in a privately-held company, Research Funding; Incyte: Consultancy, Honoraria; Galecto: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Research Funding. Rittscher: Ground Truth Labs Ltd.: Current equity holder in private company. Royston: Johnson & Johnson: Consultancy; Ground Truth Labs Ltd.: Consultancy.
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