title: Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia.
abstract: 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 emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.
authors.affiliation: Section of Haematology/Oncology, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724 USA.
authors.forename: A F
authors.initials: AF
authors.lastname: List
authors.forename: C S
authors.initials: CS
authors.lastname: Spier
authors.forename: T M
authors.initials: TM
authors.lastname: Grogan
authors.forename: C
authors.initials: C
authors.lastname: Johnson
authors.forename: D J
authors.initials: DJ
authors.lastname: Roe
authors.forename: J P
authors.initials: JP
authors.lastname: Greer
authors.forename: S N
authors.initials: SN
authors.lastname: Wolff
authors.forename: H J
authors.initials: HJ
authors.lastname: Broxterman
authors.forename: G L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: W S
authors.initials: WS
authors.lastname: Dalton
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000032:analysis; D019011:Antigens, CD7 / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology; D007951:Leukemia, Myeloid / Q000145:classification / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics / Q000401:mortality; D011379:Prognosis; D012074:Remission Induction; D012189:Retrospective Studies; D016019:Survival Analysis; D017211:Treatment Failure; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018952:Antigens, CD34; D019011:Antigens, CD7; D014408:Biomarkers, Tumor; D008942:Mitoxantrone; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein