ROLE OF NOTCH SIGNALING PATHWAY IN THE INTERACTION BETWEEN B-ACUTE LYMPHOBLASTIC LEUKEMIA CELLS AND BONE MARROW MESENCHYMAL STROMAL CELLS

B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of acute leukemia developing in the bone marrow. While many literature data are available on the role of Notch signaling in T-cell ALL biology, the importance of this molecular pathway in the development of B-ALL cells in bone marrow microenvironment is unknown so far. In this study, we used anti-Notch molecules neutralizing antibodies and γ-secretase inhibitor (GSI) XII to investigate the role of Notch signaling pathway in the promotion of human B-ALL cell survival in the presence of stromal cell support. The treatment with combinations of anti-Notch molecules neutralizing antibodies resulted in the decrease of B-ALL cell survival, either cultured alone or co-cultured in the presence of stromal cell support. Interestingly, the inhibition of Notch-3 and -4 or Jagged-1/-2 and DLL-1 resulted in a dramatic increase of apoptotic B-ALL cells by 3 days, similar to what is obtained by blocking all Notch signaling with the γ-secretase inhibitor (GSI) XII. Our data suggest that the stromal cell-mediated anti-apoptotic effect on B-lineage ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner.