Defective Notch Activation In Mesenchymal Cells Contributes To Myeloproliferative Neoplasm In Aged Mice

Increasing evidence supports important roles of the bone marrow (BM) microenvironment in the development of hematological malignancies. Recently, the non-cell autonomous role of Notch signaling has emerged as one of the key regulators of normal and malignant hematopoiesis. By using a Mx1 - Cre -mediated Rbpj gene deletion in mice (Mx1 - Cre ; R bpjf/f) as a genetic model of Notch loss-of function, we have previously discovered that loss of Rbpj in microenvironment leads to a myeloproliferative neoplasm (MPN)-like disease, which is driven by increased miR-155 expression, NF-kB activation, and inflammatory cytokine production (Wang et al . Cell Stem Cell, 2014). The Mx1 promoter is active in hematopoietic cells as well as in non-hematopoietic cells. In vitro analysis of the impact of Mx1 - Cre -induced R bpj gene deletion on BM endothelial cells (EC), mesenchymal stem cells (MSC), bone cells, andhematopoietic cells showed a greater increase of miR-155 expression in EC and MSC compared to other cell types, leading to higher production of inflammatory cytokines, in particular G-CSF and TNF-a. Comparative in vivo studies showed that EC-specific R bpj knockout mice (Tie2 - CreER ;Rbpjf/f) developed an inflammation and MPN-like disease like Mx1 - Cre ; R bpjf/f mice. However, the disease affected 80% of Tie2 - CreER ;Rbpjf/f mice (compared to 100% of Mx1 - Cre ; R bpjf/f), took longer time to develop (8-12 months vs. 4 months), and was less aggressive than in Mx1 - Cre ; R bpjf/f mice.