Dysregulated Fas and Bcl-2 Expression Leading to Enhanced Apoptosis in T Cells of Multiple Myeloma Patients

• Published in: Blood Vol. 85; no. 12; pp. 3679 - 3687
• Main Authors: Massaia, Massimo, Borrione, Paolo, Attisano, Carmela, Barral, Paola, Beggiato, Eloise, Montacchini, Laura, Bianchi, Alberto, Boccadoro, Mario, Pileri, Alessandro
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.06.1995; The Americain Society of Hematology
• Subjects: Antigens, Surface - biosynthesis; Apoptosis; Biological and medical sciences; fas Receptor; Female; Flow Cytometry; HLA-DR Antigens - analysis; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Lymphocyte Activation; Male; Medical sciences; Middle Aged; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins c-bcl-2; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Tumor Cells, Cultured; Human; Immunopathology; Malignant hemopathy; Gene expression; Myeloma; Cell surface; Antigen; Immunoglobulinopathy; Cell death; Lymphoproliferative syndrome; C-Onc gene; T-Lymphocyte; Protooncogene; Apoptosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V85.12.3679.bloodjournal85123679

We have previously reported the presence of activated (HLA-DR+) T cells in multiple myeloma (MM) patients. These cells produce high amounts of interleukin (IU-2 and interferon (IFN)-y and generate a potent antiplasma cell activity after appropriate in vitro stimulation, but they are unable in vivo to hold in check the disease. Activated T cells are highly susceptible to apoptosis, a form of programmed cell death involved in the modulation of immune responses and regulated by molecules such as Fas (CD95) and bcl-2. The aim of this study was to determine the expression of Fas and bcl-2 antigens and the susceptibility to apoptosis in T cells of MM patients. Fas+ cells were significantly higher, whereas bcl-2+ cells were significantly lower in MM patients than in the controls. MM patients with the highest number of HLA-DR+ T cells showed the highest Fas and the lowest bcl-2 expression. Two-color cytofluorometric analysis confirmed in individual cells that HLA-DR+ T cells coexpressed Fas and lacked bcl-2. Susceptibility to apoptosis was then investigated to evaluate the consequence of dysregulated Fas and bcl-2 expression. The percentage of apoptotic cells after incubation in medium alone (spontaneous apoptosis) or in the presence of methy(prednisolone (MP) or anti-Fas monoclonal antibody (triggered apoptosis) was significantly higher in MM and mainly restricted to HLA-DR+ T cells. Spontaneous apoptosis was reverted by exogenous IL-2. In conclusion, MM T cells have a dysregulated expression of Fas and bcl-2 antigens that is associated with an enhanced susceptibility to apoptosis. These data may unravel a novel mechanism by which activated MM T cells are weakened in their ability to exert an effective antitumor activity in vivo.