Tuesday, July 26, 2011
NFkappaB in CLL
The NF-κB family of transcription factors consists of p50, p52, RelA (also known as p65), c-Rel and RelB subunits. When two of these (the same two or a different two) come together as a dimer it forms an active transcription factor. Anti-apoptotic proteins including Bcl-2 family members Bfl-1 and Bcl-XL, the cellular inhibitors of apoptotic proteases (cIAPs) 1 and 2 and X-linked IAP (XIAP), are potential targets of NF-κB.
In uninduced normal cells, NF-κB dimers are bound by inhibitor of κB (IκB) proteins and sequestered in an inactive form in the cytoplasm. Consequent to BCR signalling, PKCβ activates the IκB kinase (Ikk) complex by the intermediate participation of a complex containing the proteins Carma-1, Malt1 and Bcl10, which activates the Tak1 protein kinase. Activation of Ikk by Tak1 results in IκB phosphorylation, ubiquitination and degradation, leading to activation of NF-κB. The PI-3K/Akt pathway also contributes to NF-κB activation in B cells.A
NF-κB in CLL
Nuclear-localized NF-κB is constitutively elevated in CLL cells compared to normal B and T lymphocytes. NF-κB elevation in peripheral blood CLL cells and consequent upregulation of Bcl-2, Bcl-XL and Mcl-1 may be mediated at least in part by interactions with vascular endothelial cells. DNA-bound (i.e. transcriptionally active) levels of the p65 subunit correlated well with in vitro survival of CLL cells, in vitro fludarabine resistance, Binet stage, time to first treatment and overall survival. No correlations were observed between nuclear p65 levels and IGHV, CD38 or Zap-70 status.
The Ikk inhibitor parthenolide and its derivative LC1 induces apoptosis of CLL cells. Sensitivity of individual isolates to LC1 correlate well with constitutive levels of nuclear-localized p65 subunit. A phase I clinical trial of LC1 has been initiated.
CLL cells are also induced to apoptosis by two drugs that target the NF-κB pathway in distinct ways; BAY117082, an Ikk inhibitor, and Kamebakaurin, which blocks DNA binding by p50. The Ikk inhibitor BMS-345541 also induces selective killing of CLL cells, accompanied by a decrease in constitutively active NF-κB.