Evaluation of microRNA-146a expression in acute lymphoblastic leukemia

Abstract

MicroRNAs (miRNAs) play an essential role in the development and progression of acute lymphoblastic leukemia (ALL), and could serve as disease biomarkers and therapeutic targets. The function of miR-146a in lymphoid differentiation has been here with discussed. However, the role of this miRNA in the outcome of ALL is not well understood. Peripheral blood of 48 patients with ALL and 20 age- and sex-matched healthy control subjects was used to accurately evaluate the expression of miR-146a by stem-loop Real time PCR. No statistically significant difference was found between patients and controls in total miR-146a expression. The expression of miR-146a was high (18.75%), low (27.08%) and not different (54.17%) in ALL patients. Our analysis indicated no association between the expression of miR-146a and any prognostic factors such as WBC/PLT counts, Hb, fusion genes (P190 and some translocations) with ALL type. This study revealed that miR-146a cannot be an independent factor for predicting the outcome of ALL patients. We suggest a multi-parameter analysis including miRNAs, transcription factors and critical genes to achieve a precise clinical panel for prognostic values.

Key words： miR-146a; acute lymphoblastic leukemia; prognostic marker

References

1 Béres N J, Szabű D, Kocsis D, Szűcs D, Kiss Z, Müller K E, Lendvai G, Kiss A, Arató A, Sziksz E, Vannay Á, Szabó A J, Veres G (2016). Role of Altered Expression of miR-146a, miR-155, and miR-122 in Pediatric Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis, 22(2): 327–335

2 Bottoni A, Calin G (2013). A Calin G. MicroRNAs as main players in the pathogenesis of chronic lymphocytic leukemia. MicroRNA, 2(3): 158–164

3 Contreras J, Palanichamy J, Tran T, Fernando T, Rodriguez-Malave N, Goswami N, Arboleda V A, Casero D, Rao D S (2015). MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1. Oncotarget, 6(13): 11023–11037

4 Daschkey S, Röttgers S, Giri A,Bradtke J , Teigler-Schlegel A, Meister G, Borkhardt A, Landgraf P (2013). MicroRNAs distinguish cytogenetic subgroups in pediatric AML and contribute to complex regulatory networks in AML-relevant pathways. Plos One, 8(2): 276–276

5 de Oliveira J C, Scrideli C A, Brassesco M S, Morales A G, Pezuk J A, de Paula Queiroz R, Yunes J A, Brandalise S R, Tone L G(2012). Differential miRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features. Leuk Res, 36(3): 293–298

6 Du J, Lu C, Cui G, Chen Y, He J (2013). DNA repair gene XRCC1 polymorphisms and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis. Chin J Cancer Res, 25(4): 405–415

7 Duyu M, Durmaz B, Gunduz C, Vergin C,Yilmaz Karapinar D , Aksoylar S, Kavakli K, Cetingul N, Irken G, Yaman Y, Ozkinay F, Cogulu O(2014). Prospective evaluation of whole genome microRNA expression profiling in childhood acute lymphoblastic leukemia. BioMed Research International, 2014(1):967585–967585

8 Ebert B L (2010). Genetic deletions in AML and MDS. Best Pract Res Clin Haematol, 23(4): 457–461

9 Fallah P, Arefian E, Naderi M, Aghaee-Bakhtiari S H, Atashi A, Ahmadi K, Shafiee A, Soleimani M (2013). miR-146a and miR-150 promote the differentiation of CD133+ cells into T-lymphoid lineage. Mol Biol Rep, 40(8): 4713–4719

10 Faraoni I, Antonetti F R, Cardone J, Bonmassar E (2009). miR-155 gene: a typical multifunctional microRNA. Biochimica et Biophysica Acta (BBA)-. Molecular Basis of Disease., 1792(6): 497–505

11 Ferreira A, Moura L, Tojal I, Ambrósio L, Pinto-Simões B, Hamerschlak N, Calin G A, Ivan C, Covas D T, Kashima S, Castro F A (2014). ApoptomiRs expression modulated by BCR–ABL is linked to CML progression and imatinib resistance. Blood Cells Mol Dis, 53(1): 47–55

12 Friedmann A M, Weinstein H J (2000). The role of prognostic features in the treatment of childhood acute lymphoblastic leukemia. Oncologist, 5(4): 321–328

13 Gaballa M R, Besa E C (2014). Myelodysplastic syndromes with 5q deletion: pathophysiology and role of lenalidomide. Ann Hematol, 93(5): 723–733

14 Ghose J, Bhattacharyya N P (2015). Transcriptional regulation of microRNA-100, -146a, and -150 genes by p53 and NFkB p65/RelA in mouse striatal STHdh(Q7)/ Hdh(Q7) cells and human cervical carcinoma HeLa cells. RNA Biol, 12(4): 457–477

15 Hagag A A, Nosair N A, Ghaith F M, Elshenawy E H (2014). Prognostic value of protease activated receptor-1 in children with acute lymphoblastic leukemia. Mediterr J Hematol Infect Dis, 6(1): e2014029

16 Han B W, Feng D D, Li Z G, Luo X Q, Zhang H, Li X J, Zhang X J, Zheng L L, Zeng C W, Lin K Y, Zhang P, Xu L, Chen Y Q (2011). A set of miRNAs that involve in the pathways of drug resistance and leukemic stem-cell differentiation is associated with the risk of relapse and glucocorticoid response in childhood ALL. Hum Mol Genet, 20(24): 4903–4915

17 Hauptman N, Glavac D (2013). MicroRNAs and long non-coding RNAs: prospects in diagnostics and therapy of cancer. Radiol Oncol, 47(4): 311–318

18 Jurado-Camino T, Córdoba R, Esteban-Burgos L, Hernández-Jiménez E, Toledano V, Hernandez-Rivas J A, Ruiz-Sainz E, Cobo T, Siliceo M, Perez de Diego R, Belda C, Cubillos-Zapata C, Lopez-Collazo E (2015). Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance. J Immunol, 194(2): 719–727

19 Li P, Wang X (2013). Role of signaling pathways and miRNAs in chronic lymphocytic leukemia. Chin Med J (Engl), 126(21): 4175–4182

20 Li X, Sanda T, Look A T, Novina C D, von Boehmer H (2011). Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL. J Exp Med, 208(4): 663–675

21 Mavrakis K J, Van Der Meulen J, Wolfe A L, Liu X, Mets E, Taghon T, Khan A A, Setty M, Rondou P, Vandenberghe P, Delabesse E, Benoit Y, Socci N B, Leslie C S, Van Vlierberghe P, Speleman F, Wendel H G (2011). A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Nat Genet, 43(7): 673–678

22 Mei Y, Gao C, Wang K, Cui L, Li W, Zhao X, Liu F, Wu M, Deng G, Ding W, Jia H, Li Z (2014). Effect of microRNA‐210 on prognosis and response to chemotherapeutic drugs in pediatric acute lymphoblastic leukemia. Cancer Sci, 105(4): 463–472

23 Musilova K, Mraz M (2015). MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. Leukemia, 29(5): 1004–1017

24 Naderi M, Abdul T H, Soleimani M, Shabani I, Hashemi S M (2015). A Home-brew Real-time PCR Assay for Reliable Detection and Quantification of Mature miR-122. Appl Immunohistochem Mol Morphol, 23(8):60–66

25 Portell C A, Wenzell C M, Advani A S (2013). Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharmacol, 5: 5–11

26 Rosato P, Anastasiadou E, Garg N, Lenze D, Boccellato F, Vincenti S, Severa M, Coccia E M, Bigi R, Cirone M, Ferretti E, Campese A F, Hummel M, Frati L, Presutti C, Faggioni A, Trivedi P (2012). Differential regulation of miR-21 and miR-146a by Epstein–Barr virus-encoded EBNA2. Leukemia, 26(11): 2343–2352

27 Saki N, Abroun S, Soleimani M, Mortazavi Y, Kaviani S, Arefian E (2014). The roles of miR-146a in the differentiation of Jurkat T-lymphoblasts. Hematology., 19(3): 141–147

28 Schotte D, De Menezes R X, Moqadam F A, Khankahdani L M, Lange-Turenhout E,Chen C , Pieters P, Den Boer M L(2011) MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia. Haematologica, 96(5):703–711

29 Schotte D, Lange-Turenhout E A, Stumpel D J, Stam R W, Buijs-Gladdines J G, Meijerink J P, Pieters R, Den Boer M L (2010). Expression of miR-196b is not exclusively MLL-driven but especially linked to activation of HOXA genes in pediatric acute lymphoblastic leukemia. Haematologica. 95(10):1675–1682

30 So A Y L, Zhao J L, Baltimore D (2013). The Yin and Yang of microRNAs: leukemia and immunity. Immunol Rev, 253(1): 129–145

31 Starczynowski D T, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, Hirst M, Hogge D, Marra M, Wells R A, Buckstein R, Lam W, Humphries R K, Karsan A (2010). Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype. Nat Med, 16(1): 49–58

32 Visone R, Rassenti L Z, Veronese A, Taccioli C, Costinean S, Aguda B D, Volinia S, Ferracin M, Palatini J, Balatti V, Alder H, Negrini M, Kipps T J, Croce C M (2009). Karyotype-specific microRNA signature in chronic lymphocytic leukemia. Blood, 114(18): 3872–3879

33 Wang Y, Li Z, He C, Wang D, Yuan X, Chen J, Jin J (2010). MicroRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells Mol Dis, 44(3): 191–197

34 Xiong Q, Yang Y, Wang H, Li J, Wang S, Li Y, Yang Y, Cai K, Ruan X, Yan J, Hu S, Fang X (2014). Characterization of miRNomes in acute and chronic myeloid leukemia cell lines. Genomics Proteomics Bioinformatics, 12(2): 79–91

35 Yan J, Jiang N, Huang G, Tay J L S, Lin B, Bi C, Koh G S, Li Z, Tan J, Chung T H, Lu Y, Ariffin H, Kham S K Y, Yeoh A E J, Chng W J (2013). Deregulated MIR335 that targets MAPK1 is implicated in poor outcome of paediatric acute lymphoblastic leukaemia. Br J Haematol, 163(1): 93–103

36 Yin J Y, Tang Q, Qian W, Qian J, Lin J, Wen X M,  Zhou J D, Zhang Y Y, Zhu X W, Deng Z Q (2014). Increased expression of miR-24 is associated with acute myeloid leukemia with t (8; 21). Int J Clin Exp Pathol, 7(11): 8032–8038

37 Zhang H, Luo X Q, Zhang P, Huang L B, Zheng Y S, Wu J, Zhou H, Qu L H, Xu L, Chen Y Q (2009). MicroRNA patterns associated with clinical prognostic parameters and CNS relapse prediction in pediatric acute leukemia. PLoS ONE, 4(11): e7826