Understanding the biology of CD180 in chronic lymphocytic leukemia

CD180 is an orphan toll-like receptor which is highly expressed on the surface of B cells, but differentially expressed on chronic lymphocytic leukaemia (CLL) cells from different patients. The loss of CD180 in CLL indicates that the receptor somehow confers a survival advantage for the tumour. In support of this, we found that CD180 expression was enriched in CLL cases with mutated immunoglobulin heavy chain variable genes (IGHV), a subset of patients with a superior prognosis, which confirms previous observations. We also found that higher CD180 expression in both the peripheral blood and lymph nodes was associated with superior OS in CLL.

Given the growing evidence for CD180 as a prognostic marker we next turned to addressing the potential mechanisms which may underpin the down regulation of CD180 expression. We found that CLL cells readily transcribe CD180 mRNA and that CD180 accumulates intracellularly, indicating that surface CD180 expression is blocked at the post-translational stage. CLL cells did, however, have a reduced expression of myeloid differentiation-1 (MD-1) mRNA, the satellite molecule required for cell surface CD180 expression. Moreover, CD180 negative CLL cases have reduced MD-1 protein expression. Together, these data indicate that expression MD-1 may be the limiting factor for surface CD180 expression.

We also addressed mechanistic explanations for how CD180 may promote an indolent disease course. We found that CD180 and was able to cooperate with IgD BCR to downregulate intracellular signalling kinase phosphorylation, reduce proliferation and induce apoptosis. To better understand how CD180 functions in CLL, we conducted a genome-wide correlation analysis of CD180/MD-1 in a large publicly available CLL gene expression dataset. These novel observations indicated a series of rational adaptor molecules, downstream kinases, and TFs which should be investigated to better understand how CD180 can interact with IgD and drive apoptosis.

Together, our data indicates a significant role of CD180 in CLL. Importantly, our findings establish a correlation between higher CD180 expression and favourable prognostic markers and disease characteristics, indicating its potential as a prognostic indicator for CLL. Our data provides also mechanistic explanations as to how CD180 may function alone and interact with the IgD BCR to affect CLL cell behaviour.