Lipoprotein lipase in chronic lymphocytic leukemia: function and prognostic implications

Rombout, Ans; Verhasselt, Bruno; Philippé, Jan

doi:10.1111/ejh.12789

Cited by 13 publications

(11 citation statements)

References 58 publications

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“…Our findings are further strengthened by our observation of higher levels of STAT3 in CLL lymph nodes compared to healthy controls. STAT3 drives the expression of LPL (Rozovski et al, 2015) and whilst measuring the protein levels of LPL in CLL have proven difficult (Porpaczy et al, 2013;Heintel et al, 2005), increased LPL mRNA levels have been documented [reviewed in (Rombout et al, 2016)]. High levels of LPL are strongly correlated with UM-CLL and correlate with an aggressive disease course and poor prognosis (Rosenwald et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Altered expression of metabolic pathways in CLL detected by unlabelled quantitative mass spectrometry analysis

et al. 2019

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Summary Chronic lymphocytic leukaemia (CLL) remains the most common incurable malignancy of B cells in the western world. Patient outcomes are heterogeneous and can be difficult to predict with current prognostic markers. Here, we used a quantitative label‐free proteomic technique to ascertain differences in the B‐cell proteome from healthy donors and CLL patients with either mutated (M‐CLL) or unmutated (UM‐CLL) IGHV to identify new prognostic markers. In peripheral B‐CLL cells, 349 (22%) proteins were differentially expressed between normal B cells and B‐CLL cells and 189 (12%) were differentially expressed between M‐CLL and UM‐CLL. We also examined the proteome of proliferating CLL cells in the lymph nodes, and identified 76 (~8%) differentially expressed proteins between healthy and CLL lymph nodes. B‐CLL cells show over‐expression of proteins involved in lipid and cholesterol metabolism. A comprehensive lipidomic analysis highlighted large differences in glycolipids and sphingolipids. A shift was observed from the pro‐apoptotic lipid ceramide towards the anti‐apoptotic/chemoresistant lipid, glucosylceramide, which was more evident in patients with aggressive disease (UM‐CLL). This study details a novel quantitative proteomic technique applied for the first time to primary patient samples in CLL and highlights that primary CLL lymphocytes display markers of a metabolic shift towards lipid synthesis and breakdown.

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Section: Discussionmentioning

confidence: 99%

Altered expression of metabolic pathways in CLL detected by unlabelled quantitative mass spectrometry analysis

et al. 2019

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“…Provided that CLL cells display HSPGs on their surface [ 62 ] and that LPL forms homodimers, it could occur that a bridging between leukemic B-cells and other cells expressing surface HSPGs or GPIHBP1 such as endothelial cells would be mediated by LPL. Although several groups have already speculated about it, a cell–cell bridging role for LPL in CLL pathogenesis still has to be demonstrated [ 30 , 35 , 63 ]. If such a bridging actually occurred, LPL would be pivoting between surface HSPGs on the B-CLL cell side, and either HSPGs or GPIHBP1 on their counterpart.…”

Section: Lpl In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

“…Rombout et al have found that two SNPs commonly found in LPL , rs328 (premature stop codon) and rs13702 were significantly associated with CLL outcome [ 63 ]. Although both SNPs are well-known gain-of-function mutations [ 64 , 65 ], the authors of the aforementioned study reported not to have been able to detect significant differences in LPL mRNA, protein levels, or enzymatic activity in patients carrying the SNPs [ 63 ]. How these mutations affect clinical outcome in CLL is still unclear, but whether these SNPs might have a role—if any—in LPL non-metabolic functions has not been explored yet.…”

Section: Lpl In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Lipoprotein Lipase Expression in Chronic Lymphocytic Leukemia: New Insights into Leukemic Progression

Prieto

Oppezzo

2017

Molecules

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Lipoprotein lipase (LPL) is a central enzyme in lipid metabolism. Due to its catalytic activity, LPL is involved in metabolic pathways exploited by various solid and hematologic malignancies to provide an extra energy source to the tumor cell. We and others described a link between the expression of LPL in the tumor cell and a poor clinical outcome of patients suffering Chronic Lymphocytic Leukemia (CLL). This leukemia is characterized by a slow accumulation of mainly quiescent clonal CD5 positive B cells that infiltrates secondary lymphoid organs, bone marrow and peripheral blood. Despite LPL being found to be a reliable molecular marker for CLL prognosis, its functional role and the molecular mechanisms regulating its expression are still matter of debate. Herein we address some of these questions reviewing the current state of the art of LPL research in CLL and providing some insights into where currently unexplored questions may lead to.

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“…However, emerging evidence indicates that prognosis cannot be restricted to the IGVH mutation status, and great effort is still required for identifying molecular markers of disease progression. The enhanced expression of CD38 , Lipoprotein lipase ( LPL ) and Zeta-chain-associated protein kinase 70 ( ZAP70 ) was associated to U-CLL with rapid fatal outcome 4 – 7 . Nevertheless, these genes were not proved to be reliable biomarkers for evaluating the clinical course of CLL and the effectiveness of therapy.…”

Section: Introductionmentioning

confidence: 99%

The expression of inhibitor of bruton’s tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis

Albano

Chiurazzi²,

Mimmi

et al. 2018

Cell Death Dis

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Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy with a variable clinical outcome. Biomarkers of CLL progression are required for optimising prognosis and therapy. The Inhibitor of Bruton’s tyrosine kinase—isoform α (IBTKα) gene encodes a substrate receptor of Cullin 3-dependent E3 ubiquitin ligase, and promotes cell survival in response to the reticulum stress. Searching for novel markers of CLL progression, we analysed the expression of IBTKα in the peripheral blood B-cells of CLL patients, before and after first line therapy causing remission. The expression of IBTKα was significantly increased in disease progression, and decreased in remission after chemotherapy. Consistently with a pro-survival action, RNA interference of IBTKα increased the spontaneous and Fludarabine-induced apoptosis of MEC-1 CLL cells, and impaired the cell cycle of DeFew B-lymphoma cells by promoting the arrest in G0/G1 phase and apoptosis. Consistently, RNA interference of IBTKα up regulated the expression of pro-apoptotic genes, including TNF, CRADD, CASP7, BNIP3 and BIRC3. Our results indicate that IBTKα is a novel marker of CLL progression promoting cell growth and resistance to apoptosis. In this view, IBTKα may represent an attractive cancer drug target for counteracting the therapy-resistance of tumour cells.

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Lipoprotein lipase in chronic lymphocytic leukemia: function and prognostic implications

Cited by 13 publications

References 58 publications

Altered expression of metabolic pathways in CLL detected by unlabelled quantitative mass spectrometry analysis

Altered expression of metabolic pathways in CLL detected by unlabelled quantitative mass spectrometry analysis

Lipoprotein Lipase Expression in Chronic Lymphocytic Leukemia: New Insights into Leukemic Progression

The expression of inhibitor of bruton’s tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis

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