Expression of functional lung resistance–related protein predicts poor outcome in adult T-cell leukemia

Abstract

Chemotherapy of patients with adult T-cell leukemia (ATL) has been unsuccessful. The poor outcome is thought to be caused mainly by the drug resistance of ATL cells. Lung resistance–related protein (LRP) is a novel protein associated with drug resistance. The expression of LRP messenger RNA (mRNA) was evaluated by slot blot analysis in 55 patients with ATL. Of these patients, 36 had acute, 12 chronic, and 7 lymphoma-type ATL. The expression levels of LRP mRNA were significantly higher in chronic ATL than in lymphoma-type ATL (P = .007). The expression of LRP mRNA was higher in patients with white blood cell counts above 30 000/μL (P = .038) or with abnormal lymphocyte counts above 10 000/μL (P = .007) than in the remaining patients. The enhanced efflux of [14C]doxorubicin from nuclei isolated from ATL cells that expressed high levels of LRP was inhibited by a polyclonal antibody against LRP, and the accumulation of doxorubicin in the isolated nuclei was increased by the anti-LRP antibody. In acute and lymphoma-type ATL patients, high expression of LRP mRNA at diagnosis correlated with shorter survival, and a Cox proportional hazards model showed that LRP expression is an independent prognostic factor. These findings suggest that functionally active LRP is expressed in some ATL cells and that it is involved in drug resistance and poor prognosis in ATL.