Complex chromosomal aberrations in chronic lymphocytic leukemia are associated with cellular drug and irradiation resistance

Drug resistance is a major problem in chemotherapy of chronic lymphocytic l eukemia (CLL). The genetic basis and molecular pathogenesis of drug resista nce in CLL remain poorly understood. Here, we have investigated the associa tion between chromosomal aberrations and cellular resistance of CLL cells a gainst seven drugs, gamma and ultraviolet irradiation. Samples were obtaine d from 35 patients having a classical form of B-CLL. Chromosomal aberration s were first analyzed by traditional karyotyping improved by using optimize d mitogen combinations. DNA sequence copy number changes throughout the gen ome were next screened by comparative genomic hybridization. Finally, fluor escence in situ hybridization was used to detect trisomy 12 and loss of Rb and deletions at chromosome 11. The cellular sensitivity in vitro was asses sed by the reduction of macromolecular protein synthesis measured as incorp oration of radioactive L-leucine as an endpoint. The overall analysis discl osed a statistically highly significant difference in cellular drug resista nce between patients having at least three aberrations compared with patien ts with fewer or no aberrations. This strongly indicates that complex rathe r than simple molecular mechanisms are responsible for the drug and irradia tion resistance in CLL. According to published results, complex aberrations are constantly associated with poor prognosis in CLL. We demonstrated here that complex chromosomal aberrations were associated with cellular irradia tion and drug resistance, which, on the other hand, may be responsible for the poor clinical outcome in CLL.