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KML VE KML LÖSEMİK KÖK HÜCRESİ ARASINDA MİKRORNA EKSPRESYON DEĞİŞİMLERİNİN DEĞERLENDİRİLMESİ

Year 2020, Volume: 27 Issue: 3, 315 - 321, 01.09.2020
https://doi.org/10.17343/sdutfd.624530

Abstract

Amaç:
Kronik Miyeloid Lösemi (KML), hematopoetik kök hücreden (HKH) köken alan miyeloproliferatif
bir hastalıktır. MikroRNA'lar,
transkripsiyon
sonrası
gen ekspresyonunu düzenlenleyen küçük kodlamayan RNA’lardır. miRNA’lar KML’nin progresyonunda,  lösemik kök hücre büyümesi ve tirozin kinaz
inhibitörü (TKİ) direncinin gelişmesinde hücre homeostazisini
etkilemektedirler. Bu çalışmada KML lösemik hücresi ve KML lösemik kök hücresi
(LKH) arasında değişen miRNA ekspresyon profillerinin incelenmesi amaçlanmıştır.



Gereç
ve yöntem:
KML hücre hattı olan K562 hücrelerinden,
manyetik hücre ayrımlama (MACS) yöntemi
kullanılarak
CD34+CD38- lösemik kök hücreleri ayrımlanmıştır.
Ayrımlanan LKH’lerin saflığının %85-92 arasında olduğu akım sitometri yöntemi
ile gösterilmiştir. K562 ve K562 LKH’leri arasında, gerçek zamanlı kantitatif
PCR ile kanser kök hücre ilişkili 84 adet miRNA’nın ekspresyon değişimleri
incelenmiştir.



Bulgular:
K562 ve K562 LKH’leri arasında, kök hücre ilişkili olduğu bilinen 84 adet miRNA’dan 7’sinin anlamlı
düzeyde değiştiğini gözledik (P<0,05). 
K562 LKH’lerinde
hsa-miR-29b-3p’nin ekspresyon düzeylerinde artış izlenirken; hsa-miR-320d,  hsa-miR-96-5p,
hsa-let-7e-5p, hsa-miR-17-5p, hsa-miR-181b-5p hsa-miR-423-5p
’da azalma olduğu gözlenmiştir.



Sonuç
:
KML lösemik hücreleri ile KML LKH’leri arasında proliferasyon,
eritroid farklılaşma, kendi kendini yenileme ve apoptoz sürecinde rol alan
miRNA’lar ve hedef genlerinin
ekspresyonlarındaki
değişim, hastalığın
ilerlemesinde
miRNA’larında rol
oynayabileceğini
göstermektedir. Bu nedenle
KML LKH’lerine
özgü
miRNA’ların hastalığın
progresyonunun ve TKI direncinin önlenmesi
için
yeni terapötik stratejilerin geliştirilmesinde hedef
moleküller olabileceğini
düşünmekteyiz.

Supporting Institution

İzmir Katip Çelebi Üniversitesi Bilimsel Araştırma Projeleri Koordinatörlüğü

Project Number

2016.ÖNP.SHMY.0026

Thanks

Bu çalışma 2016.ÖNP.SHMY.0026 proje numarası ile İzmir Katip Çelebi Üniversitesi Bilimsel Araştırma Projeleri Koordinatörlüğü tarafından desteklenmiştir.

References

  • 1. Comert M, Baran Y, Saydam G. Changes in molecular biology of chronic myeloid leukemia in tyrosine kinase inhibitor era. Am J Blood Res 2013;19(3):191-200. 2. Litwińska Z, Machaliński B. miRNAs in chronic myeloid leukemia: small molecules, essential function. Leuk Lymphoma 2017; 58(6):1297-1305.
  • 3. Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood 2017;129(12):1595-1606.
  • 4. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol 2018;93(3):442-459.
  • 5. Herrmann H, Cerny-Reiterer S, Gleixner KV, Blatt K, Herndlhofer S, Rabitsch W et al.CD34(+)/CD38(-) stem cells in chronic myeloid leukemia Express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin. Haematologica 2012;97(2):219-26.
  • 6. Nestal de Moraes G, Souza PS, Costas FC de F, Vasconcelos FC, Reis FRS, Maia RC. The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia. Leuk Res Treatment 2012;2012:1–19.
  • 7. Elias J, Sameer A P, Hagop K, Jorge C. Chronic myeloid leukemia: mechanisms of resistance and treatment. Hematol Oncol Clin North Am 2011;25(5):981–95.
  • 8. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011;121:396–409.
  • 9. Chu S, McDonald T, Lin A, Chakraborty S, Huang Q, Snyder DS et al.Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood 2011;118:5565–5572.
  • 10. Martiáñez Canales T, de Leeuw DC, Vermue E, Ossenkoppele GJ, Smit L. Specific Depletion of Leukemic Stem Cells: Can MicroRNAs Make the Difference? Cancers (Basel). 2017;9(7): 1-23.
  • 11. Jørgensen HG, Holyoake TL. Characterization of cancer stem cells in chronic myeloid leukaemia. Biochem Soc Trans 2007;35:1347–1351.
  • 12. Carvajal LA, Steidl U. Eliminating Cancer Stem Cells in CML with Combination Transcriptional Therapy. Cell Stem Cell 2016;19:6–8.
  • 13. Di Stefano C, Mirone G, Perna S, Marfe G. The roles of microRNAs in the pathogenesis and drug resistance of chronic myelogenous leukemia (Review). Oncol Rep 2016;35(2):614–24.
  • 14. Peláez N, Carthew RW. Biological robustness and the role of microRNAs: A network perspective. Curr Top Dev Biol 2012;99:237-255.
  • 15. Nam JW, Rissland OS, Koppstein D, Abreu-Goodger C, Jan CH, Agarwal V, Yildirim MA et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell 2014;53:1031-1043.
  • 16. Polakova KM, Koblihova J, Stopka T. Role of Epigenetics in Chronic Myeloid Leukemia. Curr Hematol Malig Rep 2013;8(2):28–36.
  • 17. Yeh CH, Moles R, Nicot C. Clinical significance of microRNAs in chronic and acute human leukemia. Mol Cancer 2016;15(1):37.
  • 18. Ferreira LAM, Capannacci J, Hokama NK, Nogueira CR, Ceccarelli M, Cerulo L et al. Circulating microRNAs expression profile in newly diagnosed and imatinib treated chronic phase-chronic myeloid leukemia. Leuk Lymphoma 2019;60(3):805-811.
  • 19. Machova Polakova K, Koblihova J, Stopka T. Role of epigenetics in chronicmyeloid leukemia. Curr Hematol Malig Rep 2013;8(1):28-36.
  • 20. Venturini L, Battmer K, Castoldi M, Schultheis B, Hochhaus A, Muckenthaler MU et al. Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood 2007;109(10):4399–405.
  • 21. Machová Poláková K, Lopotová T, Klamová H, Burda P, Trněný M, Stopka T et al. Expression patterns of microRNAs associated with CML phases and their disease related targets. Mol Cancer 2011;10:41.
  • 22. Flamant S, Richie W, Guilhot J, Hols J, Bonnet ML, Chomel JC et al. Micro-RNA response to imatinib mesylate in patients with chronic myeloid leukemia. Haematologica 2010;95:1325–1333.
  • 23. Enériz ESJ, Román-Gómez J, Jiménez-Velasco A, Garate L, Maritn V, Coredu L et al. MicroRNA expression profiling in imatinib-resistant chronic myeloid leukemia patients without clinically significant ABLI-mutations. Mol Cancer 2009;8:69–72.
  • 24. Li Y, Wang H, Tao K, Xiao Q, Huang Z, Zhong L et al. miR-29b suppresses CML cell proliferation and induces apoptosis via regulation of BCR/ABL1 protein. Exp Cell Res 2013;319(8):1094–1101.
  • 25. Zofia L, Machalinski B. miRNAs in chronic myeloid leukemia: small molecules, essential function. Leukemia & Lymphoma 2016;58(6):1297-1305.
  • 26. Mott J, Kobayashi S, Bronk SF, Gores JG. miR-29 Regulates Msl-1 Protein Expression and Apoptosis. Oncogene 2007;26(42):6133-6140.
  • 27. Xu L, Xu Y, Jing Z, Wang X, Zha X, Zeng C et al. Altered expression pattern of miR-29a, miR29b and the target genes in myeloid leukemia. Exp Hematol Oncol 2014;3:17.
  • 28. Zhi F, Cao X, Xie X, Wang B, Dong W, Gu W et al. Identification of circulating microRNAs as potential biomarkers for detecting acute myeloid leukemia. PLoS One 2013;8(2):e56718.
  • 29. Wang B, Li W, Guo K, Xiao Y, Wang Y, Fan J. miR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients. Biochem Biophys Res Commun 2012;421(1):4-8.
  • 30. Wu PY, Zhang XD, Zhu J, Guo XY, Wang JF. Low expression of microRNA-146b-5p and microRNA-320d predicts poor outcome of large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone. Hum Pathol 2014 ;45(8):1664-73.
  • 31. Zhao J, Lu Q, Zhu J, Fu J, Chen Y. Prognostic value of miR-96 in patients with acute myeloid leukemia. Diagn Pathol 2014;9:76.
  • 32. Rokah OH, Granot G, Ovcharenko A, Modai S, Pasmanik-Chor M, Toren A et al. Downregulation of Mir-31, Mir-155, and Mir-564 in Chronic Myeloid Leukemia Cells. PlosOne 2012;7(4):1-12.
  • 33. Dell’Aversanal C, Altucci L. miRNA-mediated deregulation in leukemia. Front Genet 2012;3:252. 34. Cloonan N, Brown MK, Steptoe AL, Wani S, Chan WL, Forrest AR et al. The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol 2008;9(8):127.
  • 35. Wong P, Iwasaki M, Somervaille TC, Ficara F, Carico C, Arnold C et al. The miR-17-92 microRNA Polycistron Regulates MLL Leukemia Stem Cell Potential by Modulating p21 expression. Cancer Res 2010;70(9):3833-42.
  • 36. Kang CD, Yoo SD, Hwang BW, Kim KW, Kim DW, Kim CM et al. The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells. Leuk Res 2000; 24(6):527-34.
Year 2020, Volume: 27 Issue: 3, 315 - 321, 01.09.2020
https://doi.org/10.17343/sdutfd.624530

Abstract

Project Number

2016.ÖNP.SHMY.0026

References

  • 1. Comert M, Baran Y, Saydam G. Changes in molecular biology of chronic myeloid leukemia in tyrosine kinase inhibitor era. Am J Blood Res 2013;19(3):191-200. 2. Litwińska Z, Machaliński B. miRNAs in chronic myeloid leukemia: small molecules, essential function. Leuk Lymphoma 2017; 58(6):1297-1305.
  • 3. Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood 2017;129(12):1595-1606.
  • 4. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol 2018;93(3):442-459.
  • 5. Herrmann H, Cerny-Reiterer S, Gleixner KV, Blatt K, Herndlhofer S, Rabitsch W et al.CD34(+)/CD38(-) stem cells in chronic myeloid leukemia Express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin. Haematologica 2012;97(2):219-26.
  • 6. Nestal de Moraes G, Souza PS, Costas FC de F, Vasconcelos FC, Reis FRS, Maia RC. The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia. Leuk Res Treatment 2012;2012:1–19.
  • 7. Elias J, Sameer A P, Hagop K, Jorge C. Chronic myeloid leukemia: mechanisms of resistance and treatment. Hematol Oncol Clin North Am 2011;25(5):981–95.
  • 8. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011;121:396–409.
  • 9. Chu S, McDonald T, Lin A, Chakraborty S, Huang Q, Snyder DS et al.Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood 2011;118:5565–5572.
  • 10. Martiáñez Canales T, de Leeuw DC, Vermue E, Ossenkoppele GJ, Smit L. Specific Depletion of Leukemic Stem Cells: Can MicroRNAs Make the Difference? Cancers (Basel). 2017;9(7): 1-23.
  • 11. Jørgensen HG, Holyoake TL. Characterization of cancer stem cells in chronic myeloid leukaemia. Biochem Soc Trans 2007;35:1347–1351.
  • 12. Carvajal LA, Steidl U. Eliminating Cancer Stem Cells in CML with Combination Transcriptional Therapy. Cell Stem Cell 2016;19:6–8.
  • 13. Di Stefano C, Mirone G, Perna S, Marfe G. The roles of microRNAs in the pathogenesis and drug resistance of chronic myelogenous leukemia (Review). Oncol Rep 2016;35(2):614–24.
  • 14. Peláez N, Carthew RW. Biological robustness and the role of microRNAs: A network perspective. Curr Top Dev Biol 2012;99:237-255.
  • 15. Nam JW, Rissland OS, Koppstein D, Abreu-Goodger C, Jan CH, Agarwal V, Yildirim MA et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell 2014;53:1031-1043.
  • 16. Polakova KM, Koblihova J, Stopka T. Role of Epigenetics in Chronic Myeloid Leukemia. Curr Hematol Malig Rep 2013;8(2):28–36.
  • 17. Yeh CH, Moles R, Nicot C. Clinical significance of microRNAs in chronic and acute human leukemia. Mol Cancer 2016;15(1):37.
  • 18. Ferreira LAM, Capannacci J, Hokama NK, Nogueira CR, Ceccarelli M, Cerulo L et al. Circulating microRNAs expression profile in newly diagnosed and imatinib treated chronic phase-chronic myeloid leukemia. Leuk Lymphoma 2019;60(3):805-811.
  • 19. Machova Polakova K, Koblihova J, Stopka T. Role of epigenetics in chronicmyeloid leukemia. Curr Hematol Malig Rep 2013;8(1):28-36.
  • 20. Venturini L, Battmer K, Castoldi M, Schultheis B, Hochhaus A, Muckenthaler MU et al. Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood 2007;109(10):4399–405.
  • 21. Machová Poláková K, Lopotová T, Klamová H, Burda P, Trněný M, Stopka T et al. Expression patterns of microRNAs associated with CML phases and their disease related targets. Mol Cancer 2011;10:41.
  • 22. Flamant S, Richie W, Guilhot J, Hols J, Bonnet ML, Chomel JC et al. Micro-RNA response to imatinib mesylate in patients with chronic myeloid leukemia. Haematologica 2010;95:1325–1333.
  • 23. Enériz ESJ, Román-Gómez J, Jiménez-Velasco A, Garate L, Maritn V, Coredu L et al. MicroRNA expression profiling in imatinib-resistant chronic myeloid leukemia patients without clinically significant ABLI-mutations. Mol Cancer 2009;8:69–72.
  • 24. Li Y, Wang H, Tao K, Xiao Q, Huang Z, Zhong L et al. miR-29b suppresses CML cell proliferation and induces apoptosis via regulation of BCR/ABL1 protein. Exp Cell Res 2013;319(8):1094–1101.
  • 25. Zofia L, Machalinski B. miRNAs in chronic myeloid leukemia: small molecules, essential function. Leukemia & Lymphoma 2016;58(6):1297-1305.
  • 26. Mott J, Kobayashi S, Bronk SF, Gores JG. miR-29 Regulates Msl-1 Protein Expression and Apoptosis. Oncogene 2007;26(42):6133-6140.
  • 27. Xu L, Xu Y, Jing Z, Wang X, Zha X, Zeng C et al. Altered expression pattern of miR-29a, miR29b and the target genes in myeloid leukemia. Exp Hematol Oncol 2014;3:17.
  • 28. Zhi F, Cao X, Xie X, Wang B, Dong W, Gu W et al. Identification of circulating microRNAs as potential biomarkers for detecting acute myeloid leukemia. PLoS One 2013;8(2):e56718.
  • 29. Wang B, Li W, Guo K, Xiao Y, Wang Y, Fan J. miR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients. Biochem Biophys Res Commun 2012;421(1):4-8.
  • 30. Wu PY, Zhang XD, Zhu J, Guo XY, Wang JF. Low expression of microRNA-146b-5p and microRNA-320d predicts poor outcome of large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone. Hum Pathol 2014 ;45(8):1664-73.
  • 31. Zhao J, Lu Q, Zhu J, Fu J, Chen Y. Prognostic value of miR-96 in patients with acute myeloid leukemia. Diagn Pathol 2014;9:76.
  • 32. Rokah OH, Granot G, Ovcharenko A, Modai S, Pasmanik-Chor M, Toren A et al. Downregulation of Mir-31, Mir-155, and Mir-564 in Chronic Myeloid Leukemia Cells. PlosOne 2012;7(4):1-12.
  • 33. Dell’Aversanal C, Altucci L. miRNA-mediated deregulation in leukemia. Front Genet 2012;3:252. 34. Cloonan N, Brown MK, Steptoe AL, Wani S, Chan WL, Forrest AR et al. The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol 2008;9(8):127.
  • 35. Wong P, Iwasaki M, Somervaille TC, Ficara F, Carico C, Arnold C et al. The miR-17-92 microRNA Polycistron Regulates MLL Leukemia Stem Cell Potential by Modulating p21 expression. Cancer Res 2010;70(9):3833-42.
  • 36. Kang CD, Yoo SD, Hwang BW, Kim KW, Kim DW, Kim CM et al. The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells. Leuk Res 2000; 24(6):527-34.
There are 34 citations in total.

Details

Primary Language Turkish
Subjects Clinical Sciences
Journal Section Research Articles
Authors

Melek Pehlivan This is me

Mustafa Soyöz

Hatice İlayhan Karahan Çöven This is me

Burcu Çerçi This is me

Tülay Kılıçaslan Ayna

Halil Ateş This is me

Zeynep Yüce This is me

Hakkı Ogün Sercan This is me

Project Number 2016.ÖNP.SHMY.0026
Publication Date September 1, 2020
Submission Date September 26, 2019
Acceptance Date December 5, 2019
Published in Issue Year 2020 Volume: 27 Issue: 3

Cite

Vancouver Pehlivan M, Soyöz M, Karahan Çöven Hİ, Çerçi B, Kılıçaslan Ayna T, Ateş H, Yüce Z, Sercan HO. KML VE KML LÖSEMİK KÖK HÜCRESİ ARASINDA MİKRORNA EKSPRESYON DEĞİŞİMLERİNİN DEĞERLENDİRİLMESİ. Med J SDU. 2020;27(3):315-21.

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