Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1

Abstract

Multiple myeloma (MM) is a deadly hematopoietic malignancy characterized by proliferation of malignant plasma cells in the bone marrow (BM) and bone disease. Interactions between myeloma and BM cells facilitate tumor progression and resistance to therapies. CXCR4 and its ligand Stromal cell-derived factor-1 (SDF-1) have a primary role in this process and are associated with poor prognosis. The Notch pathway is active in myeloma cells, resulting in increased proliferation, resistance to apoptosis and osteolytic activity. We hypothesized that the CXCR4/SDF-1 axis mediates the effects of Notch signals in myeloma cells. Here we show that Notch positively controls CXCR4/SDF-1 expression and functions in myeloma cell lines, and that forced CXCR4 activation partially rescues tumor cells from the outcomes of Notch inhibition. Additionally, we provide evidences that Notch blocking in vivo significantly reduces BM infiltration by human myeloma cells in mouse xenografts. This is the first evidence that a Notch-targeted approach effectively prevents MM cell migration, proliferation and resistance to apoptosis by reducing CXCR4 and SDF-1 levels.

HES1 activation suppresses proliferation of leukemia cells in acute myeloid leukemia

“…In contrast, a definite role for Notch pathway in the development of AML is less clear. Chiaramonte reported that Notch pathway was not activated in AML [13]. Similarly, Kannan and Lobry reported that Notch was silenced in AML [6,7].…”

Targeting Tumor Initiating Cells through Inhibition of Cancer Testis Antigens and Notch Signaling: A Hypothesis

“…Aberrations in Notch signaling have also been linked to several hematological malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), lymphoma and multiple myeloma (MM) [6,12]. The role of Notch signaling in hematopoiesis and in hematopoietic SC (HSC) development and maintenance has been extensively reviewed by Bigas and Espinosa [30], the fundamental finding being that activation of the Notch pathway is necessary for HSCs maintenance, and its inhibition results in HSCs differentiation and depletion [31].…”

“…Notch signaling is dependent on cell-to-cell communication and is activated when Notch ligands, present on the "sending cell", bind to Notch receptor on the "receiving cell". MyoD in myogenesis and E2A in B lymphopoiesis), the pre-TCR alpha (which participates in regulating the T cell progenitors differentiation), cell cycle regulatory genes such as cyclin D2, cyclin D1, p21 and p27, and genes from different chemokine systems [11,12,13].…”

Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment

“…1,23 Notch signaling has been involved in the regulation of the expression and function of the CXCR4/SDF1 chemokine axis crucial for MM cell growth, survival, and migration. 24 Jagged2 increased the release of interleukin 6, vascular endothelial growth factor (VEGF), and insulin-growth factor 1 from BM stroma, factors known to promote MM cell survival, growth, and BM angiogenesis. 21 Notch signaling has been also implicated in the development of MM-associated bone disease, primarily through the stimulation of osteoclastogenesis.…”