CD26 expression correlates with a reduced sensitivity to 2′-deoxycoformycin-induced growth inhibition and apoptosis in T-cell leukemia/lymphomas

Purpose and Experimental Design: dCF (2'-deoxycofor-mycin) is a potent inhibitor of ADA (adenosine deaminase), an enzyme regulating intra- and extracellular concentrations of purine metabolites. ADA exists as cytosolic and extracellular forms, the latter colocalized on the cell surface with CD26. Once the surface expression of CD26 and ADA in a panel of cell lines and primary samples of T-cell leukemia/lymphoma was defined, we correlated this expression with the antiproliferative and apoptotic effect of dCF. Results: Surface expression of CD26 inversely correlated with the capability of dCF to inhibit cell growth and induce apoptosis both in T-cell lines and primary samples of T-cell malignancies. This conclusion was sustained by a decreased sensitivity to dCF-mediated proapoptotic and/or antiproliferative in vitro effects of: (a) leukemia/lymphoma T-cell lines expressing surface CD26/ADA complex; (b) primary CD26(+) T cell malignancies; and (c) normal T cells (CD26(+)) as compared with tumor T cells (CD26(-)) in unpurified samples from three cases of T-cell receptor gammadelta(+) T-cell malignancies characterized by a mixture of normal and neoplastic cells. This latter point was confirmed in vivo, in a patient affected by CD26(-) T-cell receptor gammadelta(+) hepatosplenic gammadelta(+) T-cell lymphomas treated on a compassionate basis with dCF. The inverse correlation between CD26 expression and sensitivity to dCF was also demonstrated in a lymphoblastic lymphoma case in which CD26 was expressed on circulating blasts at relapse but not at diagnosis, as well as in two H9 T-cell clones expressing or not expressing CD26 mRNA and protein. Conclusions: This study corroborates the notion of CD26 as a marker of poor prognosis for T-cell malignancies and delineates a role for CD26 as a predictor of poor response to dCF.