A Mutation in the Promoter of the Multidrug Resistance Gene ( MDR1 ) in Human Hematological Malignancies may Contribute to the Pathogenesis of Resistant Disease

摘要: The overexpression of the multidrug resistance gene MDR1 has been found to be associated with therapy-resistance in hematological malignancies. Yet cellular mechanisms underlying this increased expression are completely unknown. Point mutations promoter have osteogenic sarcoma (Stein et al., Eur J Cancer, 30A: 1541–1545, 1994). We therefore analyzed DNA from malignancies for point mutations. Two pairs overlapping PCR primers were designed which did not amplify MDR3 gene. Amplified was screened using single strand conformation polymorphism (SSCP). 139 patients and 93 normal controls studied. Fifteen (11%) abnormal bands on SSCP analysis. Of these, 9 had acute myeloid leukemia (AML), 4 chronic lymphocytic (CLL), 1 (ALL), nonHodgkin’s lymphoma (NHL). Sequence analysis revealed that all heterozygous a mutation (T-C transition at +8). Four normals (4%) mutation. Confirmation performed by oligonucleotide probe hybridization. All but two AML died due chemoresistant disease (one is lost followup). CLL patients, one alive progressive disease, others died. Further studies will assess effect transcription.