IGHV unmutated CLL B cells are more prone to spontaneous apoptosis and subject to environmental prosurvival signals than mutated CLL B cells

• Published in: Leukemia Vol. 25; no. 5; pp. 828 - 837
• Main Authors: Coscia, M, Pantaleoni, F, Riganti, C, Vitale, C, Rigoni, M, Peola, S, Castella, B, Foglietta, M, Griggio, V, Drandi, D, Ladetto, M, Bosia, A, Boccadoro, M, Massaia, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2011; Nature Publishing Group
• Subjects: 631/208/737; 631/80/82/23; 692/699/67/1990/283/1895; Adult; Aged; Aged, 80 and over; Apoptosis; B cells; B-cell receptor; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Bcl-2 protein; Biological and medical sciences; Blotting, Western; Bone marrow; Cancer Research; CD40 antigen; CD40 Ligand - metabolism; Chronic lymphocytic leukemia; Critical Care Medicine; Cytokines; Development and progression; Electrophoretic Mobility Shift Assay; Female; Genetic aspects; Health aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - genetics; Immunoglobulins; In vivo methods and tests; Intensive; Interleukin 4; Internal Medicine; Laboratories; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes (mononuclear); Ligands; Lymphatic leukemia; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Mutation - genetics; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Oncology; original-article; Peripheral blood mononuclear cells; Physiological aspects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors, Antigen, B-Cell - metabolism; Signal Transduction; Stromal cells; Therapeutic applications; Tumor cells; Tumor Cells, Cultured; Italy; chronic lymphocytic leukemia; immunoglobulin mutational status; tumor microenvironment; Human; Heavy peptide chain; Immunoglobulins; Hematology; Variable region; Spontaneous; Cell microenvironment; Malignant hemopathy; B-Lymphocyte; Signal transduction; Chronic lymphocytic leukemia; Cell death; Lymphoproliferative syndrome; Environment; Genetics; Mutation; Cancer; Apoptosis
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2011.12

Tumor cells in chronic lymphocytic leukemia (CLL) are more prone to apoptosis when cultured ex vivo, because they lack prosurvival signals furnished in vivo via B-cell receptor (BCR)-dependent and -independent pathways. This study compared the susceptibility of unmutated (UM) and mutated (M) CLL B cells to spontaneous apoptosis and prosurvival signals. UM CLL B cells showed a significantly higher rate of spontaneous apoptosis than M CLL B cells. Nuclear factor-kB (NF-kB) was rapidly inactivated, and B-cell leukemia/lymphoma 2 (Bcl-2) expression progressively down-regulated in the UM CLL B cells. CD40-Ligand, interleukin-4 and stromal cells significantly improved their viability and partially recovered Bcl-2, but not NF-kB expression. Peripheral blood mononuclear cells also offered protection of UM CLL B cells, and recovered both NF-kB and Bcl-2 expression. T cells, rather than nurse-like cells, were responsible for protecting UM CLL B cells by means of cell-to-cell contact and soluble factors. Despite their more aggressive features, UM CLL B cells are more susceptible to spontaneous apoptosis and depend from environmental prosurvival signals. This vulnerability of UM CLL B cells can be exploited as a selective target of therapeutic interventions.