Expression of the human major vault protein LRP in acute myeloid leukemia.
Overexpression of a 110-kD protein (lung resistance-related protein [LRP]) may predict a poor response to chemotherapy in patients with acute myeloid leukemia (AML) and ovarian carcinoma. The LRP gene has recently been mapped to chromosome 16, close to the multidrug resistance-associated protein (MRP) gene. Seventy-seven samples from 67 patients with AML were examined for expression of LRP, MRP, and multidrug resistance (MDR1) mRNA using a semiquantitative reverse transcription polymerase chain reaction (RT-PCR) assay. Results were compared with 29 normal samples (11 normal peripheral blood and 18 normal bone marrow). Thirty-three patients with untreated AML were evaluable for response to chemotherapy. Levels of LRP, but not of MRP or MDR1 mRNA, were significantly higher in eight patients who failed to achieve complete remission (CR) compared with 25 patients who achieved CR (p = 0.033). A positive correlation was demonstrated between LRP and MRP (R = 0.368, p = 0.001) and between MRP and MDR1 mRNA levels (R = 0.301, p = 0.01) in the 77 clinical samples analyzed. In AML samples, a significant difference in MDR1 mRNA levels was found between presentation (47 samples) and relapse (30 samples) (p = 0.031). No significant difference was seen in LRP mRNA levels between these two groups or in eight patients studied sequentially at both presentation and relapse. Thirteen samples (10 at presentation, 3 at relapse) were analyzed for LRP protein expression by flow cytometry. Eight (5 at presentation, 3 at relapse) displayed greater than 10% positive cells (range 15-86%). These data suggest that LRP gene overexpression may constitute a novel mechanism of multidrug resistance.
Hart
S M
SM
Department of Haematology, Royal Free Hospital and School of Medicine, London, England.
Ganeshaguru
K
K
Scheper
R J
RJ
Prentice
H G
HG
Hoffbrand
A V
AV
Mehta
A B
AB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000208:Acute Disease; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D002648:Child; D018432:Drug Resistance, Multiple; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D014407:Tumor Cells, Cultured; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics*; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein