Expression and Prognostic Significance of MDR and IAP-Family Genes in Patients with Acute Myeloid Leukemia

Introduction. Refractory Acute Myeloid Leukemia (AML) is associated with very bad prognosis. One of the major reason of induction chemotherapy failure is the expression of genes and proteins responsible for multidrug resistance (Multidrug Resistance 1 - MDR1, Multidrug Resistance-Related Protein 1 - MRP1, Breast Cancer Resistance Protein-BCRP, Lung Cancer Related Protein - LRP) and apoptosis (IAP-family genes: XIAP, cIAP1, cIAP2, survivin). The aim of the study was the evaluation of the influence of MDR and IAP-family genes expression on results of chemotherapy in patients (pts) with AML.

Material and methods. The study was performed in 45 pts (20 females and 25 males; ranged from 18 to 82 years - mean 51.2) with newly diagnosed AML. There were following types acc. FAB classification: M0–1, M1–5, M2–13, M3–4, M4–16, M5–6 and cytogenetic risk groups: favorable-8, intermediate-29 and unfavorable-8 pts. The genes expression in leukemic cells was detected by RT-PCR method. All pts were treated with induction and consolidation therapy acc. Polish Adult Leukemia Group (PALG).

Results. The expression of MDR1 gene was detected in 47%, MRP1 in 21%, BCRP in 10%, LRP in 26% and IAP-family genes in 78% of pts. Expression of MDR1 was significantly higher in M5 (p=0.02), but expression of cIAP1 and cIAP2 in M4 type (p=0.01). There was significant difference in MDR1 expression between unfavorable and good risk cytogenetic group (p=0.03), but there was none difference between cytogenetic groups in expression of IAP-family genes. There was significant difference in MDR1 expression between pts who achieved complete remission (CR) and pts without CR (p=0.01). When the expression of MDR1 gene was associated with the expression of BCRP and LRP, CR was never obtained. In all pts with complex genetic changes (MDR1+MRP1, MDR1+BCRP+LRP, MDR1+MRP1+BCRP+LRP) CR after one course of induction chemoterapy was not obtained. There was significant difference between CR rate after one course of chemotherapy in pts without MDR genes expression or expression only one gene and in pts with expression of two or more genes (p=0.02). There was no correlation between IAP-family genes expression and CR rate. Despite of differences in post-consolidation therapy (bone marrow transplantation in some pts) expression of MDR1 and survivin genes correlated with overall surival rate (p=0.05 and 0.03, respectively).

Conclusions. Results of our studies on expression of MDR and IAP-family genes in pts with AML showed that expression of MDR genes better predicted response on induction chemotherapy than IAP genes. After confirmation on larger group of pts these findings may have important significance in defining of prognosis in AML and individualization of induction and postremission therapy, eventually with new generation of MDR modulators.