Prognostic Relevance of Lipoprotein Lipase (LPL) Expression in B-CLL.

Abstract

We investigated the pattern of lipoprotein lipase (LPL) expression in B-cell chronic lymphocytic leukemia (B-CLL) and assessed its prognostic and potential functional relevance. LPL mRNA levels in peripheral blood mononuclear cells (PBMNC) from 55 CLL patients differed by 2 orders of magnitude between cases with mutated (N=28) or unmutated (N=27) IGVH (median: 1.62 vs. 100.43 compared to normal PBMNC). LPL expression correlated strongly with IGVH mutational status (R=0.78; P<0.0001). High LPL expression (≥ 10) predicted unmutated IGVH status with an odds ratio of 128.71 (P < 0.0001) and discriminated between mutated and unmutated cases in 51 of 55 patients (93%). In an extended cohort of 104 patients, a trend for LPL as a prognostic factor regarding overall survival was found: While the median overall survival (OS) in patients with LPL expression of more than 10 was 105 months, the median OS was not reached in the low LPL group. Importantly, high LPL expression (≥ 10) was significantly associated with a short treatment-free survival (median 40 vs. 96 months, P = 0.001). By indirect immunofluorescence, LPL was detected in the cytoplasm of leukemic B-CLL cells and showed intense, large granular and punctate distribution. Fine granular and diffuse staining was observed in monocytes but no immunoreactivity was detected in T- cells. In order to compare the LPL protein expression unmutated (LPL mRNA high) and mutated (LPL mRNA low) samples from 10 patients (5 mutated and 5 unmutated) were prepared and stained under identical conditions.The intensity of intracellular immunoreactivity to LPL antibody in B-CLL cells was higher in each unmutated compared to the mutated samples. In order to investigate the association of LPL with other genes we performed gene expression profiling on 12 patient samples selected for high or low LPL yielding 251 differentially expressed genes: 171 genes associated with LPL only (group 1), 58 genes with LPL and mutational status (group 2) and 22 genes with mutational status only (group 3). While group 2 and 3 contained a number of genes previously described by Rosenwald and Klein*, a considerable number of genes associated with lipid metabolism were clustered in group 1, indicating a functional role of LPL in B-CLL cells. Our data establish LPL as a prognostic marker and suggest functional consequences of LPL overexpression in patients with B-CLL.