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Transcriptional Repression and Aberrant Signaling Pathways in CLL


Transcriptional Represssion and Aberrant Signaling Pathways in CLL


The NF-kB signaling pathway has been described as constitutively active in CLL and other B cell malignancies. However therapeutic approaches to target this pathway, while likely to be clinically effective, are still under development. Hsp90 regulates the NF-kB pathway as well as other signaling pathways that are involved in CLL pathogenesis; therefore the inhibition of Hsp90 represents an attractive treatment strategy. Also particularly important is the role of NF-kB in epigenetic silencing, and more recently the regulation of non-coding RNA, and how this translates into transcriptional regulation in CLL. However, there are still undesirable off target side effects from systemically disrupting NF-kB. More advanced targeting methods will be possible through greater understanding of exactly how this pathway functions to both activate and repress gene expression in CLL.

 Selected Papers:

Hertlein E, Wagner AJ, Jones J, Lin TS, Maddocks KJ, Towns WH 3rd, Goettl VM, Zhang X, Jarjoura D, Raymond CA, West DA, Croce CM, Byrd JC, Johnson AJ. 2010. 17-DMAG targets the NF-{kappa}B family of proteins to induce apoptosis in CLL: clinical implications of HSP90 inhibition. Blood 116(1):45-53. PMCID: PMC2904580.

Chen SS, Sherman MH, Hertlein E, Johnson AJ, Teitell MA, Byrd JC, Plass C. 2009. Epigenetic alterations in a murine model for chronic lymphocytic leukemia. Cell Cycle 8(22). PMCID: PMC2871675.

Chen SS, Raval A, Johnson AJ, Hertlein E, Liu TH, Jin VX, Sherman MH, Liu SJ, Dawson DW, Williams KE, Lanasa M, Liyanarachchi S, Lin TS, Marcucci G, Pekarsky Y, Davuluri R, Croce CM, Guttridge DC, Teitell MA, Byrd JC, Plass C. 2009. Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 106(32):13433-8. PMCID: PMC2726368.

Hertlein E, Byrd JC. 2010. Signalling to drug resistance in CLL. Best Pract Res Clin Haematol 23(1):121-31.