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

Abstract

Drug resistance is a major problem in chemotherapy of chronic lymphocytic leukemia (CLL). The genetic basis and molecular pathogenesis of drug resistance in CLL remain poorly understood. Here, we have investigated the association between chromosomal aberrations and cellular resistance of CLL cells against seven drugs, gamma and ultraviolet irradiation. Samples were obtained from 35 patients having a classical form of B-CLL. Chromosomal aberrations were first analyzed by traditional karyotyping improved by using optimized mitogen combinations. DNA sequence copy number changes throughout the genome were next screened by comparative genomic hybridization. Finally, fluorescence in situ hybridization was used to detect trisomy 12 and loss of Rb and deletions at chromosome 11. The cellular sensitivity in vitro was assessed by the reduction of macromolecular protein synthesis measured as incorporation of radioactive L-leucine as an endpoint. The overall analysis disclosed a statistically highly significant difference in cellular drug resistance between patients having at least three aberrations compared with patients with fewer or no aberrations. This strongly indicates that complex rather than simple molecular mechanisms are responsible for the drug and irradiation 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 irradiation and drug resistance, which, on the other hand, may be responsible for the poor clinical outcome in CLL.

Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine

“…We show that B-CLL patients with complex karyotype have shorter TFS and OS as compared to those with fewer abnormalities, confirming previous clinical studies, [12][13][14] and in vitro data correlating karyotype complexity with resistance to drugs, including CdA. 11 However, as noted in the reports mentioned above, karyotype complexity did not retain an independent prognostic value in the multivariate analysis.…”

“…Complexity has been associated with in vitro drug resistance and poor outcome in B-CLL. [11][12][13] In addition, translocations recently proved to be the prognostic marker with the highest impact for an unfavorable outcome. 14 Still, the significance of translocations on outcome in CLL remains uncertain relative to IgV H mutational status or to treatment outcome after specific drugs.…”

High-resolution oligonucleotide array-CGH pinpoints genes involved in cryptic losses in chronic lymphocytic leukemia

“…DNA samples, extracted from the blood lymphocytes of a previously well-characterized CLL patient series (Koski et al, 2000;Karhu et al, 2003) were obtained from the Tampere University Hospital, Finland. All patients had blood lymphocyte counts 1 30 !…”

Surface membrane antigen expression changes induced in vitro by exogenous growth factors in chronic lymphocytic leukemia cells

“…Most patients had chromosomal aberrations, but none indicating chronic lymphoid leukemias other than typical CLL. 20 The clinical hematological data of the 33 CLL patients are illustrated in Table 1.…”