Type: Oral
Session: 506. Bone Marrow Microenvironment: The Bone Marrow Microenvironment in Disease
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Hematopoiesis, Biological Processes
Here, we show that transcription factor early B cell factor 1 (EBF1) is a key regulator of MSC function and MF niche by controlling the expression of ECM components, integrins, and proinflammatory cytokines. EBF1 expression is upregulated in MSCs from MF mouse models and MF patients. In co-culture assays, priming of mouse and human EBF1-deficient MSCs towards fibrosis-initiating cells is blunted in response to cells carrying the MPLW515L or JAK2V617F mutations identified in patients. Moreover, transplantation of hematopoietic progenitors expressing MPLW151L mutation into mice with MSC-specific deletion of Ebf1 results in reduced BM fibrosis, fewer megakaryocytes, and reduced expansion of mutant myeloid cells. We identified ITGB8 as an EBF1-regulated gene in the MSCs, which contributes to fibrotic transformation of the BM. Itgb8 deletion renders MSCs resistant to MPL mutant cells, which results in decreased expression of typical fibrotic markers such as Acta2, Col1a1 or S100a8. Most importantly, MF mice treated with ITGB8 neutralizing antibodies exhibit reduced disease burden, as indicated by decreased marrow fibrosis, significantly reduced frequencies of MPL mutant cells, and lower inflammation in the BM. Also, mice with MSC-specific deletion of ITGB8 show significantly lower BM fibrosis and reduced expansion of MF mutant cells upon transplantation with MPLW515L expressing hematopoietic progenitors confirming the phenotype observed with ITGB8 inhibition using neutralizing antibodies. Our data indicate EBF1 and ITGB8 as key mediators of MSC dysfunction and fibrotic transformation and suggest that targeting EBF1-ITGB8 axis in the MF niche may have therapeutic benefits.
Disclosures: Crispino: Alethiomics: Membership on an entity's Board of Directors or advisory committees; Cellarity: Consultancy; Syndax: Research Funding. Sheppard: Pliant Therapeutics: Consultancy; Pliant Therapeutics, Abbvie, Pfizer: Research Funding; Genentech, Amgen, , Arda: Membership on an entity's Board of Directors or advisory committees; Pliant Therapeutics: Current equity holder in private company.
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