Evaluation of miR-15a, miR-16-1, ZAP-70, Ang-2, and Bcl-2 as potential prognostic biomarkers in chronic lymphocytic leukemia

Autores

  • Tatiane Vieira Braga Clinical and Toxicological Analysis Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Fernanda Cristina Gontijo Evangelista Clinical and Toxicological Analysis Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Marie Gabriele Santiago Clinical and Toxicological Analysis Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Aline Lúcia Menezes Ferrão Clinical and Toxicological Analysis Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Tamara Dauare de Almeida Clinical and Toxicological Analysis Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Bárbara Lima da Fonseca Barbosa Clinical and Toxicological Analysis Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Sergio Schusterschitz da Silva Araujo Clinical Hospital, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Glaciano Nogueira Ribeiro Clinical Hospital, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Maria das Graças Carvalho Clinical and Toxicological Analysis Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
  • Adriano de Paula Sabino Clinical and Toxicological Analysis Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil https://orcid.org/0000-0001-8562-8689

DOI:

https://doi.org/10.1590/s2175-97902022e19332

Palavras-chave:

CLL, miR-15a, miR-16-1, Biomarkers

Resumo

Chronic lymphocytic leukemia (CLL) is a blood cancer characterized by the accumulation of clonal B-lymphocytes. This study evaluated the mRNA gene expression of miR-15a, miR-16- 1, ZAP-70, and Ang-2 by qPCR, as well as the plasma levels of Bcl-2 by Elisa immunoassay, in CLL patients and healthy controls. Significant differences were observed when comparing patients and controls regarding miR-15a (p < 0.001), miR-16-1 (p < 0.001) mRNA, Ang-2 gene expression, and Bcl-2 plasma levels (p < 0.001). When stratified by risk, differences were maintained with a significantly reduced expression in high-risk patients. A positive correlation was observed between miR-15a and platelets (R2 = 0.340; p = 0.009) as well as between Bcl-2 and leukocytes (R2 = 0.310; p = 0.019). Conversely, negative correlations were observed between ZAP-70 and platelets (R2 = - 0.334; p = 0.011), between miR-15a and lymphocytes (R2 = - 0.376; p = 0.004), as well as between miR-16-and lymphocytes (R2 = - 0.515; p = 0.00004). The data suggest that a reduction in miR-15a and miR-16-1 expressions, in addition to an overexpression of Bcl-2, are associated with the reduction in apoptosis and, consequently, to a longer survival of lymphocytes, thus contributing to lymphocyte accumulation and aggravation of the disease. By contrast, Ang-2 expression was significantly higher in A than in B + C Binet groups. This context leads to the speculation that this biomarker should be investigated in more robust studies within populations with a still relevantly indolent form of the disease in an attempt to identify those patients with a greater potential for an aggravation of the disease.

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Referências

Aguirre Palma LM, Flamme H, Gerke I, Kreuzer KA. Angiopoietins modulate survival, migration, and the components of the ang-tie2 pathway of Chronic Lymphocytic Leukaemia (CLL) cells in vitro. Cancer Microenviron. 2016;9(1):13-26.

Ahmadvand M, Eskandari M, Khakpour G, Pashaiefar H, Manoochehrabadi S, Yaghmaie M, et al. Identification of MiR-125a as a novel plasma diagnostic biomarker for chronic lymphoblastic leukemia. Clin Lab. 2019;65(3).

Bartels CL, Tsongalis GJ. Mini-reviews micrornas:novel biomarkers for human cancer. Clin Chem. 2009;55(4):623-31.

Bordin JO. Anemia hemolítica auto-imune e outras manifestações imunes da leucemia linfocítica crônica. Rev Bras Hematol Hemoter. 2005;27(4):257-62.

Braga TV, Evangelista FCG, Gomes LC, Araújo SSDS, Carvalho MDG, Sabino AP. Evaluation of MiR-15a and MiR-16-1 as prognostic biomarkers in chronic lymphocytic leukemia. Biomed Pharmacother. 2017;92:864-9.

Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, et al. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci USA. 2008;105(13):5166-71.

Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99(24):15524-9.

Chakupurakal G, Bell A, Griffiths M, Wandroo F, Moss P. Analysis of ZAP70 expression in adult acute lymphoblastic leukemia by real time quantitative PCR. Mol Cytogenet. 2012;5:22.

Chauffaille M. Cytogenetics and molecular biology in chronic lymphocytic leukemia. Rev Bras Hematol Hemoter. 2005;27(4):247-52.

Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A, et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2002;100(13):4609-14.

Cimmino A, Calin GA, Fabbri M, Iorio M V, Ferracin M, Shimizu M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005;102(39):13944-9.

Defoiche J, Debacq C, Asquith B, Zhang Y, Burny A, Bron D, et al. Reduction of B cell turnover in chronic lymphocytic leukaemia. Br J Haematol. 2008;143(2):240-7.

Degheidy HA, Gadalla SM, Farooqui MZH, Abbasi F, Arthur DC, Bauer SR, et al. Bcl-2 level as a biomarker for 13q14 deletion in CLL. Cytom. Part B - Clin Cytom. 2013;84(4):237-47.

Del Principe MI, Del Poeta G, Buccisano F, Maurillo L, Venditti A, Zucchetto A, et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood. 2006;108(3):853-861.

Dighiero G. CLL biology and prognosis. Hematology Am Soc Hematol Educ Program. 2005;1:278-84.

Gaidano G, Foà R, Dalla-Favera R. Review series Molecular pathogenesis of chronic lymphocytic leukemia. J Clin Invest. 2012;122(10):3432-3438.

Garg R, Wierda W, Ferrajoli A, Abruzzo L, Pierce S, Lerner S, et al. The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia. Cancer. 2012;118:3531-3537. doi: 10.1002/cncr.26593.

» https://doi.org/10.1002/cncr.26593

Gomes LC, Evangelista FCG, de Sousa LP, da Silva Araujo SS, das Graças Carvalho M, de Paula Sabino A. Prognosis biomarkers evaluation in chronic lymphocytic leukemia. Hematol Oncol Stem Cell Ther. 2017;10(2):57-62.

Gonçalves RP, Maia DP, Custódio RKA, Machado RPG, Duarte FB, Silva LB. Avaliação do perfil hematológico de pacientes com leucemia linfocítica crônica (LLC-B) em um hemocentro estadual. Rev Bras Hematol Hemoter. 2009;31(4):228-34.

Hallek M. Prognostic factors in chronic lymphocytic leukemia. Ann Oncol. 2008;19(Suppl 4):51-53.

Hanlon K, Rudin CE, Harries LW. Investigating the targets of MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL). PLoS One. 2009;4(9):e7169.

Huang L, Chen S, Zha X, Yang L, Li B, Yu Z, et al. Expression feature of CD3, FcεRIγ, and Zap-70 in patients with chronic lymphocytic leukemia. Hematology. 2012;17(2):71-5.

Kopparapu PK, Miranda C, Fogelstrand L, Mishra K, Andersson PO, Kanduri C, et al. MCPH1 maintains long- term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia. FEBS J. 2015;282(10):1939-52.

Maffei R, Martinelli S, Santachiara R, Rossi D, Guarnotta C, Sozzi E, et al. Angiopoietin-2 plasma dosage predicts time to first treatment and overall survival in chronic lymphocytic leukemia. Blood. 2010;116(4):584-592.

Mirzaei H, Fathullahzadeh S, Khanmohammadi R, Darijani M, Momeni F, Masoudifar A, et al. State of the art in microRNA as diagnostic and therapeutic biomarkers in chronic lymphocytic leukemia. J Cell Physiol. 2017;233(2):888-900.

Packham G, Stevenson FK. Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia. Immunology. 2005;114(4):441-9.

Richardson SJ, Matthews C, Catherwood MA, Alexander HD, Carey BS, Farrugia J, et al. ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2006;107(9):3584-92.

Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):311-22.

Rodrigues CA, Gonçalves MV, Ikoma MRV, Lorand-Metze I, Pereira AD, Farias DLC de, et al. Diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia. Rev Bras Hematol Hemoter. 2016;38(4):346-57.

Sagatys EM, Zhang L. Clinical and laboratory prognostic indicators in chronic lymphocytic leukemia. Cancer Control. 2012;19(1):18-25.

Scarfò L, Ferreri AJM, Ghia P. Chronic lymphocytic leukaemia. Crit Rev Oncol Hematol. 2016;104:169-82.

Shahjahani M, Mohammadiasl J, Noroozi F, Seghatoleslami M, Shahrabi S, Saba F, et al. Molecular basis of chronic lymphocytic leukemia diagnosis and prognosis. Cell Oncol. 2015;38(2):93-109.

Vasconcelos Y. Marcadores de prognóstico na leucemia linfocítica crônica. Rev Bras Hematol Hemoter. 2005;27(4):253-6.

Vrbacky F, Smolej L, Vroblova V, Pekova S, Hrudkova M, Cervinka M, et al. Angiopoietin-2 mRNA expression is increased in chronic lymphocytic leukemia patients with poor prognostic features. Hematology. 2010;15(4):210-4.

Wang YH1, Zou ZJ, Liu L, Zhang LN, Fang C, Zhu DX, et al. Quantification of ZAP-70 mRNA by real-time PCR is a prognostic factor in chronic lymphocytic leucemia. J Cancer Res Clin Oncol. 2012;138(6):1011-7.

Wiestner A1, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2002;101(12):4944-51.

William J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science. 2002;297(5589):2066-70.

World Medical Association. World Medical Association Declaration of Helsinki. JAMA. 2013;310(20):2191-4.

Xia Y, Lu RN, Li J. Angiogenic factors in chronic lymphocytic leukemia. Leuk Res. 2012;36(10):1211-7.

Zanette DL, Rivadavia F, Molfetta GA, Barbuzano FG, Proto-Siqueira R, Silva Jr WA, et al. miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukemia. Braz J Med Biol Res. 2007;40(11):1435-40.

Zeng Z, Wang K, Li Y, Xia N, Nie S, Lv B. et al. Down-regulation of microRNA-451a facilitates the activation and proliferation of CD4+ T cells by targeting Myc in patients with dilated cardiomyopathy. J Biol Chem. 2016;292(14):6004-13.

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Publicado

2022-12-19

Edição

v. 58 (2022)

Seção

Original Article

Licença

Copyright (c) 2022 Brazilian Journal of Pharmaceutical Sciences

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Como Citar

Evaluation of miR-15a, miR-16-1, ZAP-70, Ang-2, and Bcl-2 as potential prognostic biomarkers in chronic lymphocytic leukemia. (2022). Brazilian Journal of Pharmaceutical Sciences, 58. https://doi.org/10.1590/s2175-97902022e19332