Abstract
Abstract Recent studies have shown that overexpression of Heat Shock Factor (HSF) 1 in aneuploid tumor cells can overcome deficiencies in heat shock protein (HSP) 90-mediated protein folding and restore protein homeostasis. In this study we determined the mechanisms by which HSF1 promotes HSP90 function and CLL pathogenesis using CLL as model system. We report that HSF1 is overexpressed in CLL and treatment with triptolide (a small molecule inhibitor of HSF1) induces apoptosis in cultured and primary CLL B-cells. Mechanistically, we demonstrate that knockdown of HSF1 or its inhibition with triptolide results in the reduced association of HSP90 with its kinase co-chaperone cell division cycle 37 (CDC37), leading to the partial depletion of HSP90 client kinases, Bruton's Tyrosine Kinase (BTK), c-RAF and cyclin-dependent kinase 4 (CDK4). RNA-sequencing of control and HSF1-knockdown CLL cells revealed that HSF1 regulates the transcription of upstream modulators of the NF-kB pathway including MYD88 and TLR1. Consequently, treatment with triptolide or knockdown of HSF1 inhibits NF-kB signaling in CLL cells. In an in vivo model of CLL, tail vein injection of luciferase-expressing Mec-1 cells into Rag2-/-IL2Rγc-/- mice followed by daily intraperitoneal injection of minnelide (a pro-drug of triptolide) for 28 days reduced in vivo disease burden and conferred significant survival advantage (p<0.0003) to treated mice compared to vehicle controls. Minnelide treatment also attenuated NF-kB and BTK signaling in vivo. In conclusion, our study provides a strong rationale to target HSF1 in CLL and test the activity of minnelide against human CLL. Disclosures Saluja: Minneamrita Therapeutics: Equity Ownership.
