ÖZET

Amaç:

Akut myeloid lösemi (AML), hematopoietik kök hücrelerin farklılaşmasının bozulması ile karakterize, heterojen, malign bir hastalıktır. microRNA’lar (miRNA), AML’nin oluşumunda ve ilerlemesinde etkili olan faktörlerden biridir. mikroRNA-210’un AML’nin prognozuna etkisi ve AML gelişimdeki etki ettiği yolaklar araştırılan bir konudur. BCL-2 bir protoonkogendir ve apoptozu inhibe eden proteini kodlar. AML hücrelerinde BCL-2’nin aşırı ekspresyonu görülmektedir. Sitogenetik anormalliklerin varlığı veya yokluğu, AML’de önemli bir prognostik belirteçtir. Bu çalışmada, miRNA-210 ve BCL-2 ekspresyonlarının AML prognozu üzerindeki etkisi ve sitogenetik bulgularla ilişkisinin karşılaştırılması amaçlanmıştır.

Yöntemler:

AML'li hastalardan ve sağlıklı bireylerden alınan kemik iliği ve/veya periferal kan örneklerinde sitogenetik analizler gerçekleştirilmiş, RNA izolasyonunu takiben miR-210 ve BCL-2 mRNA seviyeleri kantitatif gerçek zamanlı polimeraz zincir reaksiyonu yöntemi (qRT-PCR) ile saptanmıştır.

Bulgular:

Sitogenetik analiz sonucu sağlıklı bireylerde herhangi bir anomaliye rastlanmazken, bazı AML’li hastalarda klonal yapısal ve sayısal anomaliler tespit edilmiştir. AML’li hastaların lökositlerindeki ve kemik iliği örneklerindeki BCL-2 mRNA ekspresyon seviyelerinin sağlıklı bireylerin lökositlerindeki ekspresyon seviyelerine göre arttığı saptanırken, miR-210 seviyeleri açısından hasta ve sağlıklı bireyler arasında bir fark bulunmamıştır. Ancak AML’li hastalara ait lökositlerin miR-210 seviyesi yine hastaların kemik iliği örneklerindeki miR-210 seviyesinden anlamlı derecede yüksek olarak saptanmıştır. Ek olarak, AML’li hastaların kemik iliği örneklerinde BCL-2 ve miR-210 arasında pozitif bir korelasyon bulunmuştur.

Sonuç:

BCL-2 mRNA ve miR-210 seviyelerinde görülen artış apoptoz mekanizmasında bozulmaya sebep olarak hastalığın prognozu üzerinde olumsuz etkiler yaratabilir.

References

Shipley JL, Butera JN. Acute myelogenous leukemia. Exp Hematol 2009;37:649-58.

Estey E, Döhner H. Acute myeloid leukaemia. Lancet 2006;368:1894-907.

Fortina P, Londin E, Park JY, Kricka LJ. Acute myeloid leukemia : methods and protocols. 2017.

WHO. ACUTE MYELOGENOUS LEUKEMIA ( Including Acute Promyelocytic Leukemia ). 2014 Rev Cancer Med 2014;(List of Essential Medicines):1-14.

Mughal T. Understanding Leukemias, Lymphomas and Myelomas [Internet]. CRC Press; 2005. Available from: https://books.google.com.tr/books?id=Z0UqBgAAQBAJ

Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet 2013;381:484-95.

Longo DL. Harrison’s hematology and oncology. New York: McGraw-Hill Medical; 2010.

Estey EH, Faderl SH, Kantarjian HM. Hematologic Malignancies: Acute Leukemias [Internet]. Springer Berlin Heidelberg; 2007. (Hematologic Malignancies). Available from: https://books.google.com.tr/books?id=im1Fdb19geUC

Yohe S. Molecular Genetic Markers in Acute Myeloid Leukemia. J Clin Med 2015 ;4:460-78.

Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev 2004 ;18:115-36.

Gao HY, Wang W, Luo XG, Jiang YF, He X, Xu P, et al. Screening of prognostic risk microRNAs for acute myeloid leukemia. Hematology 2018;23:747-55.

Harrandah AM, Mora RA, Chan EKL. Emerging microRNAs in cancer diagnosis, progression, and immune surveillance. Cancer Lett 2018;438:126-32.

Tang X, Chen L, Yan X, Li Y, Xiong Y, Zhou X. Overexpression of miR-210 is associated with poor prognosis of acute myeloid leukemia. Med Sci Monit 2015;21:3427-33.

Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ 2018;25:65-80.

Irvine AE, McMullin MF, Ong YL. Bcl-2 Family Members As Prognostic Indicators in AML. Hematology 2002;7:21-31.

Tóthová E, Fricova M, Stecová N, Kafková A, Elbertová A. High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Neoplasma 2002;49:141-4.

Wojcik I, Szybka M, Golanska E, Rieske P, Blonski JZ, Robak T, et al. Abnormalities of the P53, MDM2, BCL2 and BAX genes in acute leukemias. Neoplasma 2005;52:318-24.

Waters J. Human Cytogenetics: A Practical Approach, Volume II: Malignancy and Acquired Abnormalities (second edition). Edited by D. E. Rooney and B. H. Czepulkowski. IRL Press at Oxford University Press. 1992. 293 pages. Price Paper £22.50, ISBN 0 19963313 4. Spira. Genet Res [Internet]. 2009/04/14. 1993;61(1):76. Available from: https://www.cambridge.org/core/article/human-cytogenetics-a-practical-approach-volume-ii-malignancy-and-acquired-abnormalities-second-edition-edited-by-d-e-rooney-and-b-h-czepulkowski-irl-press-at-oxford-university-press-1992-293-pages-price-paper-2250-is

Therman E. Human Chromosomes: Structure, Behavior, Effects [Internet]. Springer-Verlag; 1980. Available from: https://books.google.com.tr/books?id=vMlqAAAAMAAJ

McGowan-Jordan J, Simons A, Schmid M. ISCN 2016: An International System for Human Cytogenomic Nomenclature (2016) [Internet]. Karger; 2016. (An International system for human cytogenetic nomenclature). Available from: https://books.google.com.tr/books?id=0y3JjwEACAAJ

Mardani R, Jafari Najaf Abadi MH, Motieian M, Taghizadeh-Boroujeni S, Bayat A, Farsinezhad A, et al. MicroRNA in leukemia: Tumor suppressors and oncogenes with prognostic potential. J Cell Physiol 2019;234:8465-86.

Huang X, Le QT, Giaccia AJ. MiR-210--micromanager of the hypoxia pathway. Trends Mol Med 2010;16:230-7.

Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, et al. hsa-miR-210 Is Induced by Hypoxia and Is an Independent Prognostic Factor in Breast Cancer. Clin Cancer Res 2008;14:1340-8.

Gee HE, Camps C, Buffa FM, Patiar S, Winter SC, Betts G, et al. hsa-mir-210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer. Cancer 2010;116:2148-58.

Ho AS, Huang X, Cao H, Christman-Skieller C, Bennewith K, Le QT, et al. Circulating miR-210 as a Novel Hypoxia Marker in Pancreatic Cancer. Transl Oncol 2010;3:109-13.

Zhao A, Li G, Péoc’h M, Genin C, Gigante M. Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp Mol Pathol 2013;94:115-20.

Qiu S, Lin S, Hu D, Feng Y, Tan Y, Peng Y. Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients. J Transl Med 2013;11:10.

Giannakakis A, Sandaltzopoulos R, Greshock J, Liang S, Huang J, Hasegawa K, et al. miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer. Cancer Biol Ther 2008;7:255-64.

Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol 2008;141:672-5.

McCormick RI, Blick C, Ragoussis J, Schoedel J, Mole DR, Young AC, et al. miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis. Br J Cancer 2013;108:1133-42.

Reed JC. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood 2008;111:3322-30. Erratum in: Blood 2008;112:452.

Thomas S, Quinn BA, Das SK, Dash R, Emdad L, Dasgupta S, et al. Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets 2013;17:61-75.

Zhou J, Chen Y, Li C, Liu W. The protein expression of Bcl-2, Bax, Fas/Apo-1 in acute myeloid leukemia. J Tongji Med Univ 1998;18:42-5.

Del Poeta G, Venditti A, Del Principe MI, Maurillo L, Buccisano F, Tamburini A, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood 2003;101:2125-31.

Mehta S V, Shukla SN, Vora HH. Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: its correlation with FLT3. Neoplasma 2013;60:666-75.

Qiu J, Zhou XY, Zhou XG, Cheng R, Liu HY, Li Y. Neuroprotective effects of microRNA-210 against oxygen-glucose deprivation through inhibition of apoptosis in PC12 cells. Mol Med Rep 2013;7:1955-9.

Chio CC, Lin JW, Cheng HA, Chiu WT, Wang YH, Wang JJ, et al. MicroRNA-210 targets antiapoptotic Bcl-2 expression and mediates hypoxia-induced apoptosis of neuroblastoma cells. Arch Toxicol 2013;87:459-68.

Lu Y, Yuan J, Wang H, Pei R, Chen Z, Jin J. [Clinical features and prognosis of acute myeloid leukemia with acquired trisomy 21]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese J Med Genet 2017;34:554-8.

Freitas PC, Carvalho-Salles AB, Mendiburu CF, Ricci OJ, Fett-Conte AC. Clonal monosomy of chromosome 21 in a case of myelodysplastic syndrome. Genet Mol Res 2011;10:2718-20.

Bacher U, Schanz J, Braulke F, Haase D. Rare cytogenetic abnormalities in myelodysplastic syndromes. Mediterr J Hematol Infect Dis 2015;7:e2015034.

Li Z, Wei H, Lin D, Zhou CL, Liu BC, Wang Y, et al. Cytogentic and prognostic characteristic of acute myeloid leukemia with monosomal karyotype. Zhonghua Xue Ye Xue Za Zhi 2016;37:366-71.

Akut Myeloid Lösemi Hastalarında mikroRNA-210 ve BCL-2 Ekspresyon Seviyeleri

ÖZET

References