Cell Surface Markers in CLL as Predictors for Time to First Treatment and Targets for the Retinoid Acitretin

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world and we conducted this study to explore which disease markers are helpful in predicting time to first treatment in CLL. We found that combining IgVH mutational analysis with testing for the high risk immunophenotypic markers CD38 and CD49d can offer a predictive tool that can differentiate between a standard risk CLL group with long treatment free survival (mutated IgVH and no co-expression of CD38 and CD49d) and a high risk group that progress early post diagnosis and usually requires multiple lines of treatment (unmutated IgVH with no expression of both CD38 and CD49d).

The retinoid acitretin was used to treat psoriasis in a patient with a known history of CLL. Post treatment with acitretin his lymphocytosis improved to normal levels. This case sparked research to investigate the effects of acitretin on CLL cells. The effect of acitretin on the expression of CD49d, CXCR4 and L-selectin was examined. CD49d, CXCR4 and L-selectin represent important cell surface proteins that control CLL cell traffic. In this study acitretin was shown to have no effect on the expression of CXCR4 or CD49d; however, acitretin significantly reduced the expression of L-selectin.

Adhesion of CLL cells to the endothelium in lymph node microenvironment and bone marrow stroma, promotes CLL cell survival and protects CLL cells from spontaneous or drug-induced apoptosis.The effects of acitretin on the adhesion of MEC-1 “CLL like” cells to the endothelium were tested using human umbilical vein endothelial cells (HUVEC). This study indicated that acitretin significantly reduced the adhesion of MEC-1 cells to the endothelium. Similar reduction in adhesion was seen when MEC-1 cells were treated with ibrutinib (BTK inhibitor licensed for CLL treatment). We found that combining ibrutinib with acitretin led to more pronounced reduction in the adhesion of MEC-1 cells to the HUVEC cells.

We finally used western blotting to evaluate if the effects of acitretin on adhesion were mediated through PI3K-p85 pathway. We found that acitretin down regulates PI3K-p85; while ibrutinib has no effect on the PI3K-p85 pathway. This suggests that down regulation of PI3k-p85 pathway can be a possible mechanism through which acitretin reduces CLL cell adhesion to the endothelium.

We conclude that acitretin; a drug licensed for the treatment of psoriasis with limited side effects may potentially be an adjunctive treatment in CLL by enhancing the effects of other anti-CLL agents