Expression of apoptosis regulators in cutaneous T-cell lymphoma (CTCL) cells

This study examined cutaneous T-cell lymphoma (CTCL) cell lines and cutaneous lesions for the presence of Bcl-2 gene family members and found that the two apoptosis-inhibiting members Bcl-xL and Mcl-1 and the two apoptosis-supporting members Bad and Bax were expressed. However, Bad was at least partially inactivated by phosphorylation. In skin lesions, the translocation of Bad from the nucleus to the cytoplasm may reflect the Bad inactivation by phosphorylation identified in vivo. Bax is also ineffective, as the non-steroidal anti-inflammatory drug sulindac, whose cytotoxic effect is mediated by Bax, could not induce apoptosis in CTCL cell lines. The expression of Bcl-2, Bcl-xL, and Mcl-1 may therefore be sufficient to guarantee the survival of malignant CTCL cells. The Bcl-x, Mcl-1, Bad, and Bax proteins were also expressed in all CTCL skin lesions tested. In two patients from whom two biopsies from two different time points of the disease were available, a significant increase in Mcl-1 expression was found in the later-stage skin lesion. Overexpression of Mcl-1 and synthesis of non-functional Bax may be responsible for the resistance of CTCL cells to the anti-cancer drugs chlorambucil and sulindac.     

Aktuelle Aspekte zur Pathogenese von Sézary-Syndrom und Mycosis fungoides

Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative skin disorders whose pathogenesis is poorly understood. Cytokines and chemokines are important factors which can modify the cutaneous microenvironment allowing the accumulation of lymphocytes. Most of these neoplasms seem to be T helper-2 cells. While interferon gamma is the natural inhibitor of clonal T-cell proliferations, interferon resistance has been recently found in these cells. This interferon resistance may be an Achilles heel that can be targeted by molecular therapeutic interventions.