Comprehensive Cellular Dissection of the Bone Marrow Microenvironment in Primary Myelofibrosis

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.200-200
• Main Authors: Sarkaria, Shawn M, Bao, Suying, Zhang, Chaolin, Ding, Lei
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-153727

Primary myelofibrosis (PMF) is a severe subtype of myeloproliferative neoplasm (MPN) characterized by progressive bone marrow (BM) fibrosis and hematopoietic insufficiency, reflecting profound pathology of the BM microenvironment. However, a comprehensive understanding of the stromal cell changes that drive BM remodeling in PMF remains lacking. We performed lineage tracing and single-cell RNA sequencing (scRNA-seq) of PMF bone marrow stromal cells to comprehensively understand the maladaptive fibrosis process. PMF was induced using two established murine transplantation models: THPO overexpression (TOE) and the clinically relevant MPLW515L mutation. LepR and Gli1 are both putative markers of mesenchymal stromal cell (MSC) populations that give rise to myofibroblasts. To assess their relative contributions to BM fibrosis, we performed a head-to-head lineage tracing comparison using Lepr-Cre; tdTomato and Gli1-CreER; tdTomato mice. Our steady-state analysis in young adult animals (6-7 weeks) demonstrated that LepR- and Gli1-lineage cells occupy largely distinct areas of long bones aside from limited overlap in the metaphysis. LepR-lineage cells were distributed uniformly throughout the bone marrow whereas Gli1-lineage cells were sparse and primarily localized near the growth plate. Under PMF conditions, LepR + cells contributed to the majority of myofibroblasts (>80%) while Gli1 + cells contributed to a minority of myofibroblasts (