Speaker: Marta Derecka, assistant member (St. Jude faculty, hematology), St. Jude Children's Research Hospital

Title: Transcriptional control of bone marrow niche in normal and pre-malignant hematopoiesis

Abstract: Hematopoietic stem cells (HSCs) and their malignant counterparts reside in a complex bone marrow (BM) microenvironment that includes mesenchymal stromal cells (MSCs). In age-related blood malignancies, hematopoietic cells carrying disease-causing mutations alter their microenvironment creating a dysfunctional niche. The defective niche is a hallmark of myelofibrosis (MF) where inflamed MSCs produce excessive amounts of extracellular matrix (ECM) causing BM fibrosis, which impairs blood cell production leading to extramedullary hematopoiesis, anemia and fatigue. While the genetic events that initiate myelofibrosis in HSCs acquiring driver mutations in JAK2, MPL or CALR are well defined, less is understood about the mechanisms responsible for BM fibrosis and niche dysfunction.

Here, we show that transcription factor early B cell factor 1 (EBF1) is a key regulator of fibrotic remodeling of BM niche in MF. EBF1 expression is upregulated in MSCs from MF mouse models and MF patients. Transplantation of hematopoietic progenitors expressing MPLW151L mutation into mice with MSC-specific deletion of Ebf1 results in reduced BM fibrosis and decreased tumor burden. We identified ITGB8 as an EBF1-regulated gene in the MSCs, which contributes to fibrotic remodeling of the BM. Itgb8 deletion renders MSCs resistant to MPL mutant cells, which results in decreased expression of fibrotic markers such as Acta2, Col1a1 or S100a8. Moreover, MF mice treated with ITGB8 neutralizing antibodies exhibit reduced disease burden, as indicated by decreased 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 cells confirming the phenotype observed with pharmacological ITGB8 inhibition. Our data indicate that targeting EBF1-ITGB8 axis in the MF niche may have therapeutic benefits.

Hosts: Clyde Campbell, GDCB assistant professor, and Raquel Espin Palazon, GDCB assistant professor