Figure 1.

Schematic overview of cellular and molecular alterations in the bone marrow microenvironment leading to hematopoietic malignancies. Mice with conditional deletion of the RNA-processing endonuclease Dicer1 in osterix but not osteocalcin-expressing osteolineage cells developed MDS-like disease and AML. Similarly, deletion of the Sbds gene from osterix-expressing (Osx+) cells augmented p53 levels followed by elevated secretion of S100A8 and A9 proinflammatory cytokines. S100A8/9 bind to toll-like receptor 4 and altered physiological properties of HSCs. Mice with constitutively active β-catenin protein in osteoblasts manifested expansion of myeloid cells and development of AML. Activated osteoblasts upregulated Jagged1 expression on their cell surface which augments Notch signaling and shifts differentiation potential of HSCs. Osteolineage and mesenchymal stroma cells with activating mutations of tyrosine phosphatase non-receptor type 11 (Ptpn11) resulted in elevated levels of the chemokine CCL3, subsequent monocyte recruitment and secretion of proinflammatory cytokines that activated HSCs and caused MPN-like disease. MPN was also developed upon deletion of the signal-induced proliferation-associated gene 1 (Sipa1) from mesenchymal stroma and endothelial cells. Endothelial cells with abrogated canonical Notch signaling resulted in development of MPN-like disease. Activation of canonical Notch signaling results in proteolytic cleavage of the Notch intracellular domain and its translocation to the nucleus to activate transcription of Notch target genes via binding to the transcription factor recombination signal binding protein for immunoglobulin κ J region (RBPJ). In the absence of Notch signals, RBPJ acts as transcriptional repressor. Deletion of RBPJ upregulated mir-155, which by targeting an inhibitor of NF-κb signaling (κB-Ras1) resulted in NF-κB activation followed by elevated levels of inflammatory cytokines, including granulocyte colony-stimulating factor and tumor necrosis factor-α. This again elevated numbers of immature myeloid cells. MSCs, mesenchymal stroma cells; OLCs, osteolineage cells; SDS, Shwachman-Diamond syndrome. This figure was created using SMART Servier Medical Art Web site.