CD180 functions in activation, survival and cycling of B chronic lymphocytic leukaemia cells

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BlankCD180 functions in activation, survival and cycling of B chronic

lymphocytic leukaemia cells.

N Porakishvili, A Memon, K Vispute, N Kulikova, EA , KR Rai, A Nathwani, RN

Damle, N Chiorazzi, and PM Lydyard

Br J Haematol, March 28, 2011;

..

School of Life Sciences, University of Westminster, London, UK University of

Washington, Seattle, WA The Feinstein Institute for Medical Research, Manhasset,

NY, USA UCL Cancer Institute, London, UK.

We previously showed that approximately 60% of B chronic lymphocytic leukaemia

(B-CLL) cells express surface CD180, an orphan receptor of the Toll-like

receptor family. Here we investigated the ability of anti-CD180 monoclonal

antibody (mAb) to induce activation, cell cycling, survival and signalling in

B-CLL cells and normal B cells. Upon addition of anti-CD180 mAb, alone or in

combination with anti-CD40 mAb or recombinant IL-4 (rIL-4), expression of CD86,

Ki-67, uptake of DiOC(6) , phosphorylation of signalling protein kinases and

Ca(2+) flux were measured in B-CLL cells from untreated patients and normal B

cells from age-matched volunteers. Normal B cells and approximately 50% of

CD180(+) B-CLL clones responded to CD180 ligation by activation, cycling and

increased survival comparable with, or superior to, those induced by anti-CD40

mAb or rIL-4 (Responder B-CLL). Non-responder CD180(+) B-CLL clones failed to

respond to CD180 mAb and responded poorly to CD40 mAb and rIL-4. Anti-CD180 mAb

induced phosphorylation of ZAP70/Syk, Erk, p38MAPK and Akt in normal B cells and

Responder B-CLL cells. In contrast, Erk, p38MAPK and Akt were not phosphorylated

in Non-responder B-CLL cells indicating a block in signalling and possible

anergy. CD180 may provide powerful expansion and survival signals for Responder

B-CLL cells and have an important prognostic value.

PMID: 21443749