Impact of the expression of P glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat shock protein 27 on response to induction therapy and long-term survival in patients with de novo acute myeloid leukemia

• Published in: Experimental hematology 2002-11, Vol.30 (11), p.1302-1308
• Main Authors: Kasimir-Bauer, Sabine, Beelen, Dietrich, Flasshove, Michael, Noppeney, Richard, Seeber, Siegfried, Scheulen, Max Ernst
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; ATP-Binding Cassette, Sub-Family B, Member 1 - analysis; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Cytarabine - administration & dosage; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Female; Follow-Up Studies; Gene Expression; Genes, bcl-2; Genes, MDR; Genes, p53; Heat-Shock Proteins - physiology; Humans; Idarubicin - administration & dosage; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - mortality; Male; Middle Aged; Neoplasm Proteins - analysis; Neoplasm Proteins - physiology; Neoplastic Stem Cells - metabolism; Prognosis; Proto-Oncogene Proteins c-bcl-2 - analysis; Proto-Oncogene Proteins c-bcl-2 - physiology; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin - administration & dosage; Tumor Cells, Cultured - metabolism; Tumor Suppressor Protein p53 - analysis; Tumor Suppressor Protein p53 - physiology
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/S0301-472X(02)00926-8

Resistance to chemotherapy-induced apoptosis and a multidrug-resistance phenotype is the major problem in the treatment of acute myeloid leukemia (AML). We recently demonstrated that the coexpression of at least two proteins, including P glycoprotein, multidrug resistance-related protein, bcl-2 (flow cytometry), p53 (luminometric immunoassay), and heat shock protein 27 (Western blotting), was predictive for response to induction therapy in de novo AML comparing leukemic blasts of 20 responders with 20 nonresponders. After long-term follow-up, we now present our evaluation on the prognostic significance of these proteins in leukemic blasts of 124 untreated AML patients with regard to the probability of remission (PoR) and overall survival (OS). Analyzing leukemic blasts obtained from bone marrow samples, we found that no single protein significantly correlated with PoR or OS. In contrast, the coexpression of at least two of these proteins was predictive for reduced OS in univariate as well as multivariate analysis. Although we could not identify any particular protein combination predictive for reduced OS, those patients with no or only one protein expressed in their leukemic blasts had a survival probability of 48% in contrast to 24% in those patients with the coexpression of two or more proteins. Among the clinical markers, only response to chemotherapy had a significant effect on OS and age was of prognostic relevance for PoR. We conclude that overexpression of only one protein possibly involved in resistance, is not sufficient to influence the prognosis for long-term survival in AML, whereas the expression of more than one protein is predictive for reduced OS. Protein combination seems to be individually different, and targeting only one protein in further clinical trials may not help to overcome multifactorial resistance.