Interaction with vascular endothelium enhances survival in primary chronic lymphocytic leukemia cells via NF-{kappa}B activation and de novo gene transcription.

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Blank Interaction with vascular endothelium enhances survival in primary chronic

lymphocytic leukemia cells via NF-{kappa}B activation and de novo gene

transcription.

AG Buggins, C Pepper, PE Patten, S Hewamana, S Gohil, J Moorhead, N Folarin, D

Yallop, NS , GJ Mufti, C Fegan, and S Devereux

Cancer Res, August 24, 2010; .

Haematological Medicine, King's College London.

Chronic lymphocytic leukemia (CLL) cells rapidly undergo apoptosis in vitro

suggesting that the in vivo microenvironment provides crucial anti-apoptotic

signals. Over expression of the anti-apoptotic proteins Bcl-2 and Mcl-1 is a

hallmark of CLL and their expression is further enhanced in the lymphoid

tissues. However, the high levels of Mcl-1 found in peripheral blood samples,

coupled with its short half-life, led us to hypothesize that it must be actively

maintained in the peripheral circulation. Co-culture of CLL cells with human

vascular endothelial cells significantly enhanced tumor cell survival, an effect

that was not observed with normal B-cells. This was associated with elevated

levels of the anti-apoptotic proteins Bcl-2, Mcl-1 and Bcl-XL and marked

increased expression of CD38 and CD49d both of which are associated with

clinically aggressive disease. Since CD38, CD49d and some Bcl-2 family genes are

transcriptional targets for NF-kappaB, we assessed NF-kappaB activation

following co-culture with endothelial cells. DNA binding of the NF-kappaB

subunit Rel A was significantly increased and strongly correlated with changes

in transcription of CD38, CD49d, BCL2, MCL1 and BCLXL; effects that were

reversed by a peptide inhibitor of Rel A. These effects were not observed

following co-culture with non-endothelial cell lines. Therefore, CLL cells

receive specific survival signals following interaction with endothelial cells

mediated through the activation of NF-kappaB and the induction of downstream

target genes. This type of interaction in the peripheral vasculature may explain

the constitutive NF-kappaB activation and the over-expression of Bcl-2 family

proteins commonly seen in this disease.

PMID: 20736369