Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow–derived mesenchymal stromal cells

• Published in: Blood Vol. 118; no. 2; pp. 380 - 389
• Main Authors: Nwabo Kamdje, Armel Hervé, Mosna, Federico, Bifari, Francesco, Lisi, Veronica, Bassi, Giulio, Malpeli, Giorgio, Ricciardi, Mario, Perbellini, Omar, Scupoli, Maria Teresa, Pizzolo, Giovanni, Krampera, Mauro
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 14.07.2011; Americain Society of Hematology
• Subjects: Apoptosis - genetics; B-Lymphocytes - pathology; Biological and medical sciences; Bone Marrow Cells - metabolism; Bone Marrow Cells - physiology; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Calcium-Binding Proteins - physiology; Cell Communication - genetics; Cell Communication - physiology; Hematologic and hematopoietic diseases; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - physiology; Jagged-1 Protein; Jagged-2 Protein; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - physiology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; Receptor, Notch3; Receptor, Notch4; Receptors, Notch - genetics; Receptors, Notch - metabolism; Receptors, Notch - physiology; Serrate-Jagged Proteins; Signal Transduction - genetics; Signal Transduction - physiology; Stromal Cells - metabolism; Stromal Cells - physiology; Tumor Cells, Cultured; Human; Notch receptor; Hematology; Malignant hemopathy; B-Lymphocyte; Mesenchymal cell; Precursor B cell acute lymphoblastic leukemia; Signal transduction; Cell contact; Cell death; Lymphoproliferative syndrome; Bone marrow; Stromal cell; Cancer; Apoptosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-12-326694

Although many literature data are available on the role of Notch signaling in T-cell acute lymphoblastic leukemia (ALL) biology, the importance of this molecular pathway in the development of B-lineage ALL (B-ALL) cells in the BM microenvironment is unknown so far. In this study, we used anti-Notch molecules neutralizing Abs and γ-secretase inhibitor (GSI) XII to investigate the role of the Notch signaling pathway in the promotion of human B-ALL cell survival in presence of stromal cell support. The treatment with combinations of anti-Notch molecule neutralizing Abs resulted in the decrease of B-ALL cell survival, either cultured alone or cocultured in presence of stromal cells from normal donors and B-ALL patients. 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 GSI XII. Our data suggest that the stromal cell–mediated antiapoptotic effect on B- ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner.