MDR1, MRP, TOPOISOMERASE-II-ALPHA BETA, AND CYCLIN-A GENE-EXPRESSION IN ACUTE AND CHRONIC LEUKEMIAS/

Gene expression was analyzed by cDNA-PCR at the mRNA level in bone mar row samples (>80% blasts) from ALL (28 primary, 22 first relapses, 10 recurrent relapses), from AML (14 primary, 23 relapses), in peripheral blood lymphocytes from CLL (five untreated, 10 treated), in one CML i n blast crisis in the course of the disease (four samples), and in bon e marrow samples from healthy donors (12 specimens). We found low mean MDR1 expression in primary ALL, first relapses of ALL, and primary AM L. Significantly higher mean relative MDR1 expression levels were seen in recurrent relapses of ALL, and in the group of relapsed state AML. MDR1 expression measured intermediate in bone marrow samples from hea lthy donors. The CLL lymphocytes showed generally relatively high MDR1 expression levels. MRP gene expression measured very similar in prima ry ALL, first relapses of ALL, primary AML, and normal bone marrow. Si gnificantly increased MRP mRNA levels were observed in the groups of r ecurrent ALL and relapsed state AML. CLL lymphocytes also showed high MRP expression levels. A combined increase of MDR1 (about 20-fold) and MRP (about four-fold) was monitored in samples obtained from the CML in blast crisis after chemotherapy. While no significant differences o f the mean topoisomerase II beta mRNA levels were found throughout, a significantly decreased topoisomerase II alpha gene expression was mea sured in first and recurrent relapses of ALL. In CLL lymphocytes eithe r the expression of the topoisomerase II alpha gene was not detectable by cDNA-PCR, or it measured very low. Topoisomerase II alpha gene exp ression was correlated to cyclin A gene expression in the samples of a cute leukemias, indicating the link of topoisomerase II alpha expressi on to the proliferative activity of these leukemic blast cells. Our re sults point to a potentially multifactorial emergence of multidrug res istance in particular states and types of leukemias.