Abstract

Genome-wide gene expression profiling of chronic lymphocytic leukemia (CLL) cells in comparison to healthy donor CD5-positive B-cells revealed deregulated expression of lipase-associated genes. A set of 19 lipase activity defined genes, e.g. LPL, phospholipases A1, −A2, −C and −D2 family members and other lipase-associated genes were overexpressed in CLL. Recently lipoprotein lipase (LPL) was identified as prognostic factor in CLL. Here we show that the expression of LPL in CLL is induced by B-cell receptor (BCR) stimulus both in mutated and unmutated CLL samples. In native and BCR-stimulated CD5+ healthy B-cells no LPL-expression was detected. Antigenic stimulation via the BCR is thought to be functionally and prognostically relevant in CLL pathogenesis, LPL expression in CLL cells could reflect a permanent BCR-stimulus due to autoantigens including also unmutated IgVH cases.

We hypothesized that the overexpression of lipases and especially of LPL reveals a putative therapeutic target by lipase inhibition through the the FDA-approved obesity drug and lipase inhibitor orlistat (tetrahydrolipstatin), which is known to inhibit LPL as well. Treatment of CLL cells with orlistat in vitro revealed significant cytotoxicity and induction of apoptosis in primary CLL cells with an IC50 of 5.48 μM (n=18). In comparison, no significant cytotoxicity was seen with healthy PBMC’s (n=12; p<0.001), even using high doses of orlistat up to 100 μM. Induction of apoptosis induction was observed both in low-risk (ZAP70 negative, n=15) and high-risk (ZAP70-positive, n=10) CLL samples. Orlistat mediated cytotoxicity was slightly decreased by BCR stimulus while additive cytotoxic effects where observed in combination with fludarabine treatment. Susceptibility to orlistat treatment was not dependent on Binet stage.

In summary, we provide in vitro data for a criticial role of fatty acid metabolism in CLL pathogenesis and suggest a therapeutic potential of the lipase inhibitor orlistat. No severe systemic side effects of orlistat have been observed in several animal models and in the current clinical application as anti-obesity drug. Orlistat seems to be a promising candidate for an anti-leukemic therapy in CLL, ongoing in vivo experiments applying the TCL1 mouse model will further elucidate the therapeutic potential of orlistat.

Disclosure: No relevant conflicts of interest to declare.

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