Overexpression of the Fas-inhibitory molecule TOSO–a novel antiapoptotic factor in chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is characterised by resistance to apoptotic stimuli, mediated by overexpression of anti-apoptotic factors or extracellular survival signals. In this context, TOSO, also known as Fas-inhibitory molecule 3, was identified as a candidate gene over-expressed in CLL. TOSO is a transmembrane protein that inhibits Fas-mediated apoptosis by binding Fas-associated death domain via its C-terminal intracellular domain. In CLL, high levels of TOSO expression have been correlated with more aggressive disease, being associated with high leukocyte count, advanced Binet stage, need for chemotherapy and unmutated IgV_H gene status. Also, the CD38⁺ CLL subset with proliferative activity showed enhanced TOSO expression. B-cell receptor-stimulation was identified as positive regulator of TOSO expression, potentially providing a functional mechanism for aberrant TOSO expression in CLL. In contrast, CD40-ligand signalling reduces expression of TOSO, possibly explaining previously observed Fas-sensitisation by CD40-ligand in gene therapy trials. Both the association with unmutated IgV_H gene status and the specific induction of TOSO via the BCR suggest autoreactive BCR signalling involving TOSO as a mediator of resistance to apoptosis in CLL. Further studies will reveal the functional context of TOSO in CLL and B cell biology. Surface expression of TOSO will enable antibody-based targeting of this novel CLL-antigen.

Keywords:

• TOSO
• FAIM3
• chronic lymphocytic leukemia
• apoptosis
• Fas