Association of Expression and Ratio with Clinical and Molecular Prognostic Markers in Chronic Lymphocytic Leukemia

Overview

Journal J Med Biochem

Specialty Biochemistry

Date 2017 Mar 31

PMID 28356875

Citations 32

Authors

Ksenija Vucicevic

Vladimir Jakovljevic

Natasa Colovic

Natasa Tosic

Tatjana Kostic

Irena Glumac

Sonja Pavlovic

Teodora Karan-Djurasevic

Milica Colovic

Affiliations

Soon will be listed here.

Abstract

Background: In chronic lymphocytic leukemia (CLL), apoptotic resistance of malignant B lymphocytes results, in part, from the intrinsic defects of their apoptotic machinery. These include genetic alterations and aberrant expression of many apoptosis regulators, among which the family members play a central role.

Aim: The aim of this study was to investigate the association of pro-apoptotic gene expression and ratio with the clinical features of CLL patients as well as with molecular prognostic markers, namely the mutational status of rearranged immunoglobulin heavy variable (IGHV) genes and lipoprotein lipase () gene expression.

Methods: We analyzed the expression of mRNA and mRNA ratio in the peripheral blood mononuclear cells of 58 unselected CLL patients and 10 healthy controls by the quantitative reverse-transcriptase polymerase chain reaction.

Results: We detected significant gene overexpression in CLL samples compared to non-leukemic samples (p=0.003), as well as an elevated ratio (p=<0.001). Regarding the association with prognostic markers, the ratio showed a negative correlation to lymphocyte doubling time (r=-0.307; p=0.0451), while high-level expression was associated with -positive status (p=0.035). Both the expression of and ratio were higher in patients with unmutated vs. mutated IGHV rearrangements, but this difference did not reach statistical significance.

Conclusions: Our results suggest that dysregulated expression of and , which leads to a high ratio in leukemic cells, contributes to the pathogenesis and clinical course of CLL.

Citing Articles

Neurodegenerative diseases and neuroinflammation-induced apoptosis.

Huang S, Lu Y, Fang W, Huang Y, Li Q, Xu Z Open Life Sci. 2025; 20(1):20221051.

PMID: 40026360 PMC: 11868719. DOI: 10.1515/biol-2022-1051.

Analyzing gene-based apoptotic biomarkers in insomnia using bioinformatics.

Zhu W, Yang X, Li N, Zhang B, Huang L, Cheng H Medicine (Baltimore). 2025; 104(3):e40965.

PMID: 39833072 PMC: 11749514. DOI: 10.1097/MD.0000000000040965.

Elucidating the mechanism of stigmasterol in acute pancreatitis treatment: insights from network pharmacology and / experiments.

Zhao X, Li F, Wen A, Yu X, Xu X, Wan C Front Pharmacol. 2025; 15:1485915.

PMID: 39764471 PMC: 11701227. DOI: 10.3389/fphar.2024.1485915.

Cremastrae Pseudobulbus Pleiones Pseudobulbus (CPPP) Against Non-Small-Cell Lung Cancer: Elucidating Effective Ingredients and Mechanism of Action.

Cao Y, Hao Z, Liu M, Xue J, Wang Y, Wang Y Pharmaceuticals (Basel). 2024; 17(11).

PMID: 39598428 PMC: 11597303. DOI: 10.3390/ph17111515.

A Machine Learning Approach to Gene Expression in Hypertrophic Cardiomyopathy.

Pavic J, Zivanovic M, Tanaskovic I, Pavic O, Stankovic V, Virijevic K Pharmaceuticals (Basel). 2024; 17(10).

PMID: 39459004 PMC: 11510441. DOI: 10.3390/ph17101364.

References

Nuckel H, Huttmann A, Klein-Hitpass L, Schroers R, Fuhrer A, Sellmann L . Lipoprotein lipase expression is a novel prognostic factor in B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2006; 47(6):1053-61. DOI: 10.1080/10428190500464161. View

Meijerink J . t(14;18), a journey to eternity. Leukemia. 1998; 11(12):2175-87. DOI: 10.1038/sj.leu.2400849. View

Osorio L, Aguilar-Santelises M, de Santiago A, Hachiya T, Mellstedt H, Jondal M . Increased serum levels of soluble Fas in progressive B-CLL. Eur J Haematol. 2001; 66(5):342-6. DOI: 10.1034/j.1600-0609.2001.066005342.x. View

Ringshausen I, Schneller F, Bogner C, Hipp S, Duyster J, Peschel C . Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta. Blood. 2002; 100(10):3741-8. DOI: 10.1182/blood-2002-02-0539. View

Messmer B, Messmer D, Allen S, Kolitz J, Kudalkar P, Cesar D . In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest. 2005; 115(3):755-64. PMC: 548318. DOI: 10.1172/JCI23409. View

Van Bockstaele F, Pede V, Janssens A, Callewaert F, Offner F, Verhasselt B . Lipoprotein lipase mRNA expression in whole blood is a prognostic marker in B cell chronic lymphocytic leukemia. Clin Chem. 2006; 53(2):204-12. DOI: 10.1373/clinchem.2006.076331. View

Kravic-Stevovic T, Bogdanovic A, Bumbasirevic V . Higher percentage of in vitro apoptotic cells at time of diagnosis in patients with chronic lymphocytic leukemia indicate earlier treatment requirement: ten years follow up. Srp Arh Celok Lek. 2014; 142(1-2):48-53. DOI: 10.2298/sarh1402048k. View

Kitada S, Andersen J, Akar S, Zapata J, Takayama S, Krajewski S . Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood. 1998; 91(9):3379-89. View

Vant Veer M, Brooijmans A, Langerak A, Verhaaf B, Goudswaard C, Graveland W . The predictive value of lipoprotein lipase for survival in chronic lymphocytic leukemia. Haematologica. 2006; 91(1):56-63. View

10.

Lekovic D, Mihaljevic B, Kraguljac-Kurtovic N, Peruncic-Jovanovic M, Bogdanovic A, Colovic M . [Prognostic significance of new biological markers in chronic lymphocytic leukaemia]. Srp Arh Celok Lek. 2012; 139(11-12):753-8. DOI: 10.2298/sarh1112753l. View

11.

Karan-Djurasevic T, Palibrk V, Zukic B, Spasovski V, Glumac I, Colovic M . Expression of Bcl2L12 in chronic lymphocytic leukemia patients: association with clinical and molecular prognostic markers. Med Oncol. 2013; 30(1):405. DOI: 10.1007/s12032-012-0405-7. View

12.

Kienle D, Korz C, Hosch B, Benner A, Mertens D, Habermann A . Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes. J Clin Oncol. 2005; 23(16):3780-92. DOI: 10.1200/JCO.2005.02.568. View

13.

Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas J, Sanchez A, Martin-Saavedra F . A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia. 2004; 18(8):1391-400. DOI: 10.1038/sj.leu.2403398. View

14.

Obermann E, Went P, Tzankov A, Pileri S, Hofstaedter F, Marienhagen J . Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase. J Clin Pathol. 2006; 60(7):794-7. PMC: 1995795. DOI: 10.1136/jcp.2006.040956. View

15.

Chiorazzi N, Ferrarini M . Evolving view of the in-vivo kinetics of chronic lymphocytic leukemia B cells. Hematology Am Soc Hematol Educ Program. 2006; :273-8, 512. DOI: 10.1182/asheducation-2006.1.273. View

16.

Morales A, Olsson A, Celsing F, Osterborg A, Jondal M, Osorio L . High expression of bfl-1 contributes to the apoptosis resistant phenotype in B-cell chronic lymphocytic leukemia. Int J Cancer. 2004; 113(5):730-7. DOI: 10.1002/ijc.20614. View

17.

Faderl S, Keating M, Do K, Liang S, Kantarjian H, OBrien S . Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). Leukemia. 2002; 16(6):1045-52. DOI: 10.1038/sj.leu.2402540. View

18.

Kern C, Cornuel J, Billard C, Tang R, Rouillard D, Stenou V . Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood. 2003; 103(2):679-88. DOI: 10.1182/blood-2003-02-0540. View

19.

Veronese L, Tournilhac O, Verrelle P, Davi F, Dighiero G, Chautard E . Low MCL-1 mRNA expression correlates with prolonged survival in B-cell chronic lymphocytic leukemia. Leukemia. 2007; 22(6):1291-3. DOI: 10.1038/sj.leu.2405052. View

20.

Packham G, Stevenson F . Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia. Immunology. 2005; 114(4):441-9. PMC: 1782118. DOI: 10.1111/j.1365-2567.2005.02117.x. View