Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia

作者：Alan F. List, CS Spier, TM Grogan, C Johnson, DJ Roe, JP Greer, Steven N. Wolff, H J Broxterman, G L Scheffer, RJ Scheper, WS Dalton · 发表于：Blood · 年份：1996 · DOI：10.1182/blood.v87.6.2464.bloodjournal8762464 · 被引用次数：244 · 研究领域：Drug Transport and Resistance Mechanisms、Hemoglobinopathies and Related Disorders、Pharmacological Effects and Toxicity Studies

The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein-negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergenc...