Skip to main content
Top
Published in: Pathology & Oncology Research 1/2017

01-01-2017 | Original Article

Lipoprotein Lipase as a Prognostic Marker in Chronic Lymphocytic Leukemia

Authors: Zoltán Mátrai, Hajnalka Andrikovics, Anikó Szilvási, András Bors, András Kozma, Emma Ádám, Gabriella Halm, Éva Karászi, Attila Tordai, Tamás Masszi

Published in: Pathology & Oncology Research | Issue 1/2017

Login to get access

Abstract

The marked clinical heterogeneity of CLL makes early prognosis assessment important. Lipoprotein lipase (LPL) has been shown to confer adverse prognosis in CLL, recent data indicating it might also contribute to CLL cell survival and metabolism. We determined LPL mRNA expression in unselected peripheral blood of 84 CLL patients by RT PCR. Results were correlated with other prognostic markers and outcome. 30/84 (40 %) of cases were LPL positive based on the cutoff established by ROC analysis. In LPL positive patients significantly shorter median survival (136 vs 258 months, p < 0.0001) and time to first treatment intervals (36 vs 144 months, p < 0.002) were documented. LPL values correlated with male gender, higher stages, more treatment requirement, CD38 positivity and unmutated IgVH genes. Among cases with 13q deletion, LPL positivity identified a subcohort with poor outcome (median survival 108 months vs NR, p < 0.0001). In multivariate analysis, cytogenetic aberrations and LPL had significant impact on survival. Our results confirm that LPL is a strong predictor of outcome in CLL, able to improve prognostic accuracy in good risk cytogenetic subgroups. The relationship between its prognostic and functional role in CLL needs to be explored further.
Literature
1.
go back to reference Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94(6):1848–1854PubMed Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94(6):1848–1854PubMed
2.
go back to reference Damle RN, Wasil T, Fais F et al (1999) IgV Gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847PubMed Damle RN, Wasil T, Fais F et al (1999) IgV Gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847PubMed
3.
go back to reference Chiorazzi N (2012) Implications of new prognostic markers in chronic lymphocytic leukemia. Hematology 2012:76–87PubMed Chiorazzi N (2012) Implications of new prognostic markers in chronic lymphocytic leukemia. Hematology 2012:76–87PubMed
4.
go back to reference Kröber A, Seiler T, Benner A, Bullinger L, Brückle E, Lichter P, Döhner H, Stilgenbauer S (2002) VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410–1416PubMed Kröber A, Seiler T, Benner A, Bullinger L, Brückle E, Lichter P, Döhner H, Stilgenbauer S (2002) VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410–1416PubMed
5.
go back to reference Rosenwald A, Alizadeh AA, Widhopf G et al (2001) Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 194(11):1639–1647CrossRefPubMedPubMedCentral Rosenwald A, Alizadeh AA, Widhopf G et al (2001) Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 194(11):1639–1647CrossRefPubMedPubMedCentral
6.
go back to reference Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, Freedman A, Inghirami G, Cro L, Baldini L, Neri A, Califano A, Dalla-Favera R (2001) Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194(11):1625–1638CrossRefPubMedPubMedCentral Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, Freedman A, Inghirami G, Cro L, Baldini L, Neri A, Califano A, Dalla-Favera R (2001) Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194(11):1625–1638CrossRefPubMedPubMedCentral
7.
go back to reference Oppezzo P, Vasconcelos Y, Settegrana C et al (2005) The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 106(2):650–657CrossRefPubMed Oppezzo P, Vasconcelos Y, Settegrana C et al (2005) The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 106(2):650–657CrossRefPubMed
8.
go back to reference Heintel D, Kienle D, Shehata M et al (2005) High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia. Leukemia 19(7):1216–1223CrossRefPubMed Heintel D, Kienle D, Shehata M et al (2005) High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia. Leukemia 19(7):1216–1223CrossRefPubMed
9.
go back to reference Nückel H, Hüttmann A, Klein-Hitpass L, Schroers R, Führer A, Sellmann L, Dührsen U, Dürig J (2006) Lipoprotein lipase expression is a novel prognostic factor in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 47(6):1053–1061CrossRefPubMed Nückel H, Hüttmann A, Klein-Hitpass L, Schroers R, Führer A, Sellmann L, Dührsen U, Dürig J (2006) Lipoprotein lipase expression is a novel prognostic factor in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 47(6):1053–1061CrossRefPubMed
10.
go back to reference van’t Veer MB, Brooijmans AM, Langerak AW et al (2006) The predictive value of lipoprotein lipase for survival in chronic lymphocytic leukemia. Haematologica 91(1):56–63PubMed van’t Veer MB, Brooijmans AM, Langerak AW et al (2006) The predictive value of lipoprotein lipase for survival in chronic lymphocytic leukemia. Haematologica 91(1):56–63PubMed
11.
go back to reference Van Bockstaele F, Pede V, Janssens A, Callewaert F, Offner F, Verhasselt B, Philippé J (2007) Lipoprotein lipase mRNA expression in whole blood is a prognostic marker in B cell chronic lymphocytic leukemia. Clin Chem 53(2):204–212CrossRefPubMed Van Bockstaele F, Pede V, Janssens A, Callewaert F, Offner F, Verhasselt B, Philippé J (2007) Lipoprotein lipase mRNA expression in whole blood is a prognostic marker in B cell chronic lymphocytic leukemia. Clin Chem 53(2):204–212CrossRefPubMed
12.
go back to reference Nikitin EA, Malakho SG, Biderman BV et al (2007) Expression level of lipoprotein lipase and dystrophin genes predict survival in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 48(5):912–922CrossRefPubMed Nikitin EA, Malakho SG, Biderman BV et al (2007) Expression level of lipoprotein lipase and dystrophin genes predict survival in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 48(5):912–922CrossRefPubMed
13.
go back to reference Xu W, Li JY, Shen QD, Wu YJ, Yu H, Fan L (2009) Expression level of lipoprotein lipase in Chinese patients with chronic lymphocytic leukemia and its correlation with other prognostic factors. Int J Lab Hematol 31(5):552–559CrossRefPubMed Xu W, Li JY, Shen QD, Wu YJ, Yu H, Fan L (2009) Expression level of lipoprotein lipase in Chinese patients with chronic lymphocytic leukemia and its correlation with other prognostic factors. Int J Lab Hematol 31(5):552–559CrossRefPubMed
14.
go back to reference Kaderi MA, Kanduri M, Buhl AM et al (2011) LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia. Haematologica 96(8):1153–1160CrossRefPubMedPubMedCentral Kaderi MA, Kanduri M, Buhl AM et al (2011) LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia. Haematologica 96(8):1153–1160CrossRefPubMedPubMedCentral
15.
go back to reference Kristensen L, Kristensen T, Abildgaard N et al (2015) LPL gene expression is associated with poor prognosis in CLL and closely related to NOTCH1 mutations. Eur J Haematol . doi:10.1111/ejh.1270017 Dec Kristensen L, Kristensen T, Abildgaard N et al (2015) LPL gene expression is associated with poor prognosis in CLL and closely related to NOTCH1 mutations. Eur J Haematol . doi:10.​1111/​ejh.​1270017 Dec
16.
go back to reference Mead JR, Irvine SA, Ramji DP (2002) Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med 80(12):753–769CrossRefPubMed Mead JR, Irvine SA, Ramji DP (2002) Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med 80(12):753–769CrossRefPubMed
17.
go back to reference Kuemmerle NB, Rysman E, Lombardo PS et al (2011) Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol Cancer Ther 10(3):427–436CrossRefPubMedPubMedCentral Kuemmerle NB, Rysman E, Lombardo PS et al (2011) Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol Cancer Ther 10(3):427–436CrossRefPubMedPubMedCentral
18.
go back to reference Dashnamoorthy R, Abermil N, Behesti A et al (2014) The lipid addiction of diffuse large B-cell lymphoma and potential treatment strategies with novel fatty acid synthase (FASN) small molecule inhibitors. Blood 124:4490 Dashnamoorthy R, Abermil N, Behesti A et al (2014) The lipid addiction of diffuse large B-cell lymphoma and potential treatment strategies with novel fatty acid synthase (FASN) small molecule inhibitors. Blood 124:4490
19.
go back to reference Zaidi N, Lupien L, Kuemmerle NB, Kinlaw WB, Swinnen JV, Smans K (2013) Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog Lipid Res 52(4):585–589CrossRefPubMedPubMedCentral Zaidi N, Lupien L, Kuemmerle NB, Kinlaw WB, Swinnen JV, Smans K (2013) Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog Lipid Res 52(4):585–589CrossRefPubMedPubMedCentral
20.
go back to reference Rozovski U, Grgurevic S, Bueso-Ramos C et al (2015) Aberrant LPL expression, driven by STAT3, mediates free fatty acid metabolism in CLL cells. Mol Cancer Res 13:944–953CrossRefPubMedPubMedCentral Rozovski U, Grgurevic S, Bueso-Ramos C et al (2015) Aberrant LPL expression, driven by STAT3, mediates free fatty acid metabolism in CLL cells. Mol Cancer Res 13:944–953CrossRefPubMedPubMedCentral
21.
go back to reference Rozovski U, Hazan-Halevy I, Barzilai M, Keating MJ, Estrov Z (2015) Metabolism pathways in chronic lymphocytic leukemia. Leuk Lymphoma 8:1–8 Rozovski U, Hazan-Halevy I, Barzilai M, Keating MJ, Estrov Z (2015) Metabolism pathways in chronic lymphocytic leukemia. Leuk Lymphoma 8:1–8
22.
go back to reference van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL et al (2003) Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 concerted action BMH4-CT98-3936. Leukemia 17(12):2257–2317CrossRefPubMed van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL et al (2003) Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 concerted action BMH4-CT98-3936. Leukemia 17(12):2257–2317CrossRefPubMed
23.
go back to reference Matthews C, Catherwood M, Morris TC, Alexander HD (2004) Routine analysis of IgVH mutational status in CLL patients using BIOMED-2 standardized primers and protocols. Leuk Lymphoma 45(9):1899–1904CrossRefPubMed Matthews C, Catherwood M, Morris TC, Alexander HD (2004) Routine analysis of IgVH mutational status in CLL patients using BIOMED-2 standardized primers and protocols. Leuk Lymphoma 45(9):1899–1904CrossRefPubMed
25.
go back to reference Matrai Z, Sherrington PD, Pettitt AR, Zuzel M, Cawley JC (2003) CD38 expression in CLL is a marker of cell cycling activity. Blood 102(11):671a Matrai Z, Sherrington PD, Pettitt AR, Zuzel M, Cawley JC (2003) CD38 expression in CLL is a marker of cell cycling activity. Blood 102(11):671a
26.
go back to reference Damle RN, Temburni S, Calissano C, Yancopoulos S, Banapour T, Sison C, Allen SL, Rai KR (2007) Chiorazzi N. CD38 expression labels an activated subset within chronic lymphocytic leukemia clones enriched in proliferating B cells. Blood 110:3352–3359CrossRefPubMedPubMedCentral Damle RN, Temburni S, Calissano C, Yancopoulos S, Banapour T, Sison C, Allen SL, Rai KR (2007) Chiorazzi N. CD38 expression labels an activated subset within chronic lymphocytic leukemia clones enriched in proliferating B cells. Blood 110:3352–3359CrossRefPubMedPubMedCentral
27.
go back to reference Zubiaur M, Fernández O, Ferrero E, Salmerón J, Malissen B, Malavasi F, Sancho J (2002) CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3- immune receptor tyrosine-based activation motifs. J Biol Chem 277:13–22CrossRefPubMed Zubiaur M, Fernández O, Ferrero E, Salmerón J, Malissen B, Malavasi F, Sancho J (2002) CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3- immune receptor tyrosine-based activation motifs. J Biol Chem 277:13–22CrossRefPubMed
28.
go back to reference Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al (2003) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916CrossRef Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al (2003) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916CrossRef
29.
go back to reference Strefford JC, Parker H, Parker A, Robinson H, Chaplin T, Chen X et al (2009) 13q deletion size predicts disease progression and response to treatment in patients with chronic lymphocytic leukaemia. Blood 114:671 Strefford JC, Parker H, Parker A, Robinson H, Chaplin T, Chen X et al (2009) 13q deletion size predicts disease progression and response to treatment in patients with chronic lymphocytic leukaemia. Blood 114:671
30.
go back to reference Pettitt AR, Emmens CJ, Lin K, Harris RJ (2005) Chronic lymphocytic leukaemia patients with a biallelic deletion of 13q14 have a more favourable profile of prognostic factors compared with cases that have a monoallelic 13q14 deletion. Blood 106:5019 Pettitt AR, Emmens CJ, Lin K, Harris RJ (2005) Chronic lymphocytic leukaemia patients with a biallelic deletion of 13q14 have a more favourable profile of prognostic factors compared with cases that have a monoallelic 13q14 deletion. Blood 106:5019
31.
go back to reference Hernández JA, Rodríguez AE, González M et al (2009) A high number of losses in 13q14 chromosome band is associated with a worse outcome and biological differences in patients with B-cell chronic lymphoid leukemia. Haematologica 94:364–371CrossRefPubMedPubMedCentral Hernández JA, Rodríguez AE, González M et al (2009) A high number of losses in 13q14 chromosome band is associated with a worse outcome and biological differences in patients with B-cell chronic lymphoid leukemia. Haematologica 94:364–371CrossRefPubMedPubMedCentral
33.
go back to reference Porpaczy E, Tauber S, Bilban M et al (2013) Lipoprotein lipase in chronic lymphocytic leukaemia - strong biomarker with lack of functional significance. Leuk Res 37(6):631–636CrossRefPubMed Porpaczy E, Tauber S, Bilban M et al (2013) Lipoprotein lipase in chronic lymphocytic leukaemia - strong biomarker with lack of functional significance. Leuk Res 37(6):631–636CrossRefPubMed
34.
go back to reference Mansouri M, Sevov M, Fahlgren E, Tobin G, Jondal M, Osorio L, Roos G, Olivecrona G, Rosenquist R (2010) Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity. Leuk Res 34(3):301–306CrossRefPubMed Mansouri M, Sevov M, Fahlgren E, Tobin G, Jondal M, Osorio L, Roos G, Olivecrona G, Rosenquist R (2010) Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity. Leuk Res 34(3):301–306CrossRefPubMed
35.
go back to reference Pallasch CP, Schwamb J, Konigs S, Schulz A, Debey S, Kofler D et al (2008) Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells. Leukemia 22:585–592CrossRefPubMed Pallasch CP, Schwamb J, Konigs S, Schulz A, Debey S, Kofler D et al (2008) Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells. Leukemia 22:585–592CrossRefPubMed
Metadata
Title
Lipoprotein Lipase as a Prognostic Marker in Chronic Lymphocytic Leukemia
Authors
Zoltán Mátrai
Hajnalka Andrikovics
Anikó Szilvási
András Bors
András Kozma
Emma Ádám
Gabriella Halm
Éva Karászi
Attila Tordai
Tamás Masszi
Publication date
01-01-2017
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 1/2017
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-016-0132-z

Other articles of this Issue 1/2017

Pathology & Oncology Research 1/2017 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine