Prognostic significance of multidrug resistance protein in adult T-cell leukemia

The response of adult T-cell leukemia (ATL) to chemotherapy is poor, and a major obstacle to successful treatment is intrinsic or acquired drug resist ance. To determine the clinical significance of multidrug resistance protei n (MRP) I in ATL, we studied MRP1 expression and its association with clini cal outcome. The expression of MRP1 mRNA in leukemia cells from 48 ATL pati ents was studied by slot blot analysis. The expression level of MRP1 mRNA i n chronic-type ATL was significantly higher than that in lymphoma-type ATI, (P = 0.033). There was no correlation between MRP1 expression and age, gen der, WBC count, LDH, hypercalcemia, blood urea nitrogen, or performance sta tus. However, the expression of MRP1 mRNA correlated only with peripheral b lood abnormal lymphocyte counts (P = 0.008). The transporting activity, of MRP1 was assessed using membrane vesicles. Membrane vesicles prepared from ATL cells with high expression of MRP1 mRNA showed a higher ATP-dependent l eukotriene C-4 uptake than did those with low expression of MRP1 mRNA. This uptake was almost completely inhibited by LTD4 antagonists ONO-1078 and MK 571. In acute- and lymphoma-type ATL, high expression of MRP1 mRNA at diagn osis correlated with shorter survival, and Cox regression analysis revealed that MRP1 expression was an independent prognostic factor. These findings suggest that functionally active MRP1 is expressed in some ATL cells and th at it is involved in drug resistance and has a possible causal relationship with poor prognosis in ATL. Multidrug resistance-reversing agents, such as ONO-1078 and MK571, that directly interact and inhibit the transporting ac tivity of MRP1 may be useful for treating ATL patients.