Cflar Genetic Variant Resulting In Alternate Splicing Determines Isoform Specific Production Of H-Cflar Protein and Is Predictive Of Cellular Cytoxicity Of Triptolide In Hapmap Lymphoblast and AML Cell Lines

• Published in: Blood 2013-11, Vol.122 (21), p.1287-1287
• Main Authors: Chauhan, Lata, Fridley, Brooke, Tanya, Feldberg, Ghosh, Taraswi Mitra, Bhise, Neha, Lamba, Jatinder
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.1287.1287

Triptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f. It has shown to have immunosuppressive, anti-inflammation and antineoplastic effect Triptolide also serves as a potent inhibitor against different cancer types by regulating/arresting various cell signaling mechanisms such as inducing apoptotic signals by activation of pro-apoptotic proteins, inhibiting NFkB and c-KIT pathways, suppressing the Jak2 transcription, activating MAPK8/JNK signaling and modulating the heat shock responses. Further, as many of the current drugs target p53 mediated pathway to induce growth arrest or apoptosis, dysfunction or mutation in p53 leads to resistance to chemotherapy. In such patients, triptolide provide an edge over other chemotherapeutic drugs, due to its P53 independent mode of action. Genetic subsets for pancreatic cancer cells were found to be significantly correlated with triptolide sensitivity. In recent years, Epstein-Barr-virus transformed lymphoblastoid cell lines (LCLs) that are part of Interenational HapMap project (www.hapMap.org) have been used to study drug response and genetic variation correlation. Genotype data is publically available for these HapMap LCLs, thus allowing genotype-phenotype as well as genome-wide association studies. In the present study, we used HapMap LCLs derived from 60 unrelated subjects with Caucasian ancestry to identify genetic markers that are predictive of cellular sensitivity to triptolide. Our results identified a novel QTL with SNPs on chromosome 2 with significant association with triptolide cellular sensitivity. Detailed analysis of the top 100 highly significant SNPs (observed p