siRNA basierter Screen zur Identifikation neuer Imatinib-Resistenzmechanismen bei chronischer myeloischer Leukämie

Resistance towards Imatinib is a clinically relevant problem in the treatment of chronic myelogenous leukemia. To further understand the underlying mechanisms we performed a shRNA based Screen, using die shRNA-library described by Brummelkamp et al. 2002. K562-wt cells were transfected with vectors containing the library or mock vector, followed by an incubation over three weeks with Imatinib. We were able to isolate four surviving clones and identify the following possible target genes: Transcriptional regulating factor 1(TRERF1), a transcription factor, first described in connection with steroidhormone synthesis and tamoxifenresisctance in breast cancer. BCL2-like Protein 11(Bim), a member of the Bcl-2 family, regulating apoptosis and a known resistance mechanism in CML patients if lost. Seizure-related 6 homolog (mouse)-like 2 (SEZ6L2), a surface protein, located on Chromosome 16p11.2. It has been described in the association with autism spectrum disorders. Enhancer of zeste homolog 1, a member of the polycomp group (PcG). Members of this group mediate epigenetic regulation ate the lysine residue 27 of histone H3 (H3K27).