The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia

Oppezzo, Pablo; Vasconcelos, Yuri; Settegrana, Catherine; Jeannel, Dominique; Vuillier, Françoise; Legarff-Tavernier, Magali; Kimura, Eliza Yuriko Sugano; Béchet, Stéphane; Dumas, Gérard; Brissard, Martine; Merle‐Béral, Hélène; Yamamoto, Masahiro; Dighiero, Guillaume; Davi, Frédéric

doi:10.1182/blood-2004-08-3344

Cited by 125 publications

(122 citation statements)

References 38 publications

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“…In agreement with earlier publications, [13][14][15] higher levels of leukemia cell LPL mRNA were significantly associated with a shorter survival and shorter TTT in the analysis of males and females in our CLL cohort independent of APOE status (Figures 5a-d), but this was statistically significant only in males (P ¼ 0.003 for survival and 0.005 for TTT). Likewise, in analyzing the entire cohort of males and females together, those with high LPL mRNA levels had a significantly worse survival (P ¼ 0.002) and TTT (P ¼ 0.002) (Figures 2c and d).…”

Section: Resultssupporting

confidence: 79%

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Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

et al. 2008

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Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro-or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.

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Section: Resultssupporting

confidence: 79%

“…[13][14][15] LPL is a secreted lipase that binds heparan sulfate proteoglycans on the cell surface. Furthermore, LPL binds to VLDL particles (that also bind cell surface heparan sulfate proteoglycans) and hydrolyzes VLDL triglycerides (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

et al. 2008

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“…27 We also identified LPL as CLL-specific expressed gene in agreement with previously published data. 8,28 As expected, LPL expression was found in samples from unstimulated IgV H -unmutated CLL patients, but not from healthy donor cells or BCR-unstimulated IgVH-mutated patients.…”

Section: Lipases and Lipase Activity Associated Genes Are Overexpressmentioning

confidence: 69%

“…Lipase activity was identified as a prominent pathway in CLL cells and the recently identified prognostic factor lipoprotein lipase (LPL) was seen to be specifically induced by stimulation of the BCR. 8,9 LPL is a secreted enzyme, acts at the vascular side of endothelium and plays a central role for energy supply from serum triglycerides in peripheral tissues. 10 Here, we found that the lipase inhibitor orlistat, known as an effective inhibitor of LPL, acts as a cytotoxic agent in CLL cells by its proapoptotic effects.…”

Section: Introductionmentioning

confidence: 99%

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

et al. 2007

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Constitutively activated pathways contribute to apoptosis resistance in chronic lymphocytic leukemia (CLL). Little is known about the metabolism of lipids and function of lipases in CLL cells. Performing gene expression profiling including B-cell receptor (BCR) stimulation of CLL cells in comparison to healthy donor CD5 þ B cells, we found significant overexpression of lipases and phospholipases in CLL cells. In addition, we observed that the recently defined prognostic factor lipoprotein lipase (LPL) is induced by stimulation of BCR in CLL cells but not in CD5 þ normal B cells. CLL cellular lysates exhibited significantly higher lipase activity compared to healthy donor controls. Incubation of primary CLL cells (n ¼ 26) with the lipase inhibitor orlistat resulted in induction of apoptosis, with a halfmaximal dose (IC 50 ) of 2.35 lM. In healthy B cells a significantly higher mean IC 50 of 148.5 lM of orlistat was observed, while no apoptosis was induced in healthy peripheral blood mononuclear cells (PBMCs; Po0.001). Orlistat-mediated cytotoxicity was decreased by BCR stimulation. Finally, the cytotoxic effects of orlistat on primary CLL cells were enhanced by the simultaneous incubation with fludarabine (P ¼ 0.003). In summary, alterations of lipid metabolism are involved in CLL pathogenesis and might represent a novel therapeutic target in CLL.

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“…The high expression of activation-induced cytidine deaminase mRNA is associated with unmutated IgV H gene status and unfavorable cytogenetic aberrations in CLL (38) and similar observations have been made for lipoprotein lipase A, which is an ectoenzyme not expressed in normal lymphocytes that can be analyzed by quantitative RT-PCR (39,40). However, the clinical applicability of these tests has not yet been confirmed.…”

Section: Zap-70 Expressionmentioning

confidence: 95%

Clinical implications of ZAP‐70 expressionin chronic lymphocytic leukemia

Bosch

Muntañola

Giné

et al. 2006

Cytometry Part B Clinical

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The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia

Cited by 125 publications

References 38 publications

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

Clinical implications of ZAP‐70 expressionin chronic lymphocytic leukemia

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