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Çocukluk Çağı T-ALL Hastalarında PTEN ve AKT1 Gen Anlatım Düzeyleri

Yıl 2020, Cilt: 3 Sayı: 3, 114 - 121, 05.11.2020

Öz

Amaç: PI3K/AKT sinyal yolağının bozulmuş aktivasyonu tümör gelişimi ile ilişkilendirilmiştir. PTEN/AKT yolağı, hücre büyümesi ve sağ kalımında kritik role sahip olup, lösemilerde kemoterapi direnci ile ilişkilendirilmiştir. Bu çalışma kapsamında, çocukluk çağı T-ALL hastalarındaki PTEN ve AKT1 gen anlatımları belirlendi ve hastalığın prognozuna olan etkisi araştırıldı. Gereç ve Yöntem: Otuz dokuz çocukluk çağı T-ALL olgusunun, tanı zamanı kemik iliği örnekleri kantitatif gerçek zamanlı PZR ile PTEN ve AKT1 genleri için tarandı. Gen anlatım düzeylerinin hastaların yaş, cinsiyet, immünfenotip, tedavi yanıtı, nüks ve sağ kalım gibi klinik verileri ile ilişkisi incelendi. Bulgular: Çalışmamızda, T-ALL hastalarında PTEN gen anlatımında kontrollere göre bir farklılık gözlenmezken, AKT1 gen anlatımının anlamlı düzeyde arttığı belirlendi (p<0,0001). Hastaların klinik özellikleri, genel ve hastalıksız sağ kalım oranları ve gen anlatım düzeyleri arasında anlamlı bir ilişki saptanmazken, indüksiyon tedavi ilişkili sağ kalım analizleri PTEN ve AKT1 gen anlatımları ile genel sağ kalım oranları arasında (sırasıyla, p=0,026 ve p=0,034 Cox regresyon analizi) anlamlı bir ilişki ortaya koyuldu. Diğer klinik parametreler ile gen anlatım düzeyleri arasında anlamlı ilişki saptanmadı. Sonuç: Çalışmamızda, T-ALL örneklerinde PTEN gen anlatımından bağımsız olarak artmış AKT1 gen anlatımının varlığı ve sağ kalım sürelerini etkilediğine dair bulgular elde edildi. Gelecekteki çalışmalar, AKT1’in hedefe yönelik tedaviler için uygun bir aday olup olmayacağını ortaya çıkaracaktır.

Destekleyen Kurum

İstanbul Üniversitesi Bilimsel Araştırma Projeleri Birimi ve İstanbul Kalkınma Ajansı, Geleceğe Yatırım: BİYOBANKA projesi

Proje Numarası

BAP Proje No: 48185 ve İstanbul Kalkınma Ajansı Proje No: TR10/15/YNK/0093

Teşekkür

Hasta materyallerinin sağlanmasındaki katkılarından dolayı Prof. Dr. Zeynep Karakaş ve Prof. Dr. Tiraje Çelkan’a teşekkür ederiz.

Kaynakça

  • 1. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49:1211–8.
  • 2. Ferrando A. Can one target T-cell ALL? Best Pract Rese. Clin Haematol. 2018;31(4);361–6.
  • 3. Okumura N, Yoshida H, Kitagishi Y, Murakami M, Nishimura Y, Matsuda S. PI3K/AKT/PTEN signaling as a molecular target in leukemia angiogenesis. Advances in Hematology. 2012.
  • 4. Mayer IA, Arteaga CL. The PI3K/AKT Pathway as a Target for Cancer Treatment. Annu Rev Med. 2016;67:11–28.
  • 5. Worby CA, Dixon JE. PTEN. Annu Rev Biochem. 2014; 83(1):641–69.
  • 6. Milella M, Falcone I, Conciatori F, Cesta Incani U, Del Curatolo A, Inzerilli N et al. PTEN: Multiple functions in human malignant tumors. Front Oncol. 2015;16(5):24.
  • 7. Wickremasinghe RG, Prentice AG, Steele AJ. Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets. Br J Haematol. 2011;153(5):545–56.
  • 8. Shi Y, Paluch BE, Wang X, Jiang X. PTEN at a glance. J Cell Sci. 2012;125(20):4687–92.
  • 9. Chalhoub N, Baker SJ. PTEN and the PI3- kinase pathway in cancer. Annu Rev Pathol. 2009;4:127–50.
  • 10. Kharas GM, Okabe R, JJ. Ganis, Gozo M, Khandan T, Paktinat M, Gilliland GD et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood. 2010;115(7):1406–15.
  • 11. Cai J, Xu L, Tang H, Yang Q, Yi X, Fang Y et al. The Role of the PTEN/PI3K/Akt Pathway on Prognosis in Epithelial Ovarian Cancer: A Meta- Analysis. Oncologist. 2014;19(5):528–35.
  • 12. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira S-M, Garcia-Echeverria C et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci. 2009;106(1):268–73.
  • 13. Panuzzo C, Crivellaro S, Carrà G, Guerrasio A, Saglio G, Morotti A. BCR-ABL promotes PTEN downregulation in chronic myeloid leukemia. PloS One. 2014;9(10):e110682.
  • 14. Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM et al. Mutation of Pten/ Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A. 1999;96(4):1563–8.
  • 15. Philip C-A, Laskov I, Beauchamp M-C, Marques M, Amin O, Bitharas J et al. Inhibition of PI3KAKT- mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. BMC Cancer. 2017;17(1):638.
  • 16. Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, Bose S. PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer. 2004;112(3):407–10.
  • 17. Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/ Akt pathway sustain primary T cell leukemia viability. J Clin Invest. 2008;118(11):3762–74.
  • 18. Mendes RD, Canté-Barrett K, Pieters R, Meijerink JPP. The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia. Haematologica. 2016;101(9):1010–7.
  • 19. Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD et al. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia. Haematologica. 2013;98(6):928–36.
  • 20. Paganin M, Grillo MF, Silvestri D, Scapinello G, Buldini B, Cazzaniga G et al. The presence of mutated and deleted PTEN is associated with an increased risk of relapse in childhood T cell acute lymphoblastic leukaemia treated with AIEOP-BFM ALL protocols. Br J Haematol. 2018;182(5):705–11.
  • 21. Weerkamp F, Baert MR, Naber BA, Koster EE, de Haas EF, Atkuri KR et al. Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules. Proc Natl Acad Sci U S A. 2006;103(9):3322-6.
  • 22. Ng OH, Erbilgin Y, Firtina S, Celkan T, Karakas Z, Aydogan G et al. Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia. Blood Cancer J. 2014;4(3):e192.
  • 23. Hoelzer D, Gökbuget N. Diagnostik und therapie der akuten lymphatischen leukämie des erwachsenen. Der Onkologe. 2002;8:672-85.
  • 24. Livak KJ, Schmittgen, TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4): 402–8.
  • 25. Hisamatsu Y, Oki E, Otsu H, Ando K, Saeki H, Tokunaga E et al. Effect of EGFR and p-AKT Overexpression on Chromosomal Instability in Gastric Cancer. Annals of Surgical Oncology. 2016;23:1986–92.
  • 26. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24(50):7455–64.
  • 27. Manning BD, Cantley LC. AKT/PKB Signaling: Navigating Downstream. Cell. 2007 Jun 29;129(7):1261–74.
  • 28. Knobbe CB, Reifenberger G. Genetic Alterations and Aberrant Expression of Genes Related to the Phosphatidyl-lnositol-3′-Kinase/ Protein Kinase B (Akt) Signal Transduction Pathway in Glioblastomas. Brain Pathology. 2006;13(4):507–18.
  • 29. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three akts. Genes Dev. 1999;13(22):2905–27.
  • 30. Sandhöfer N, Metzeler KH, Rothenberg M, Herold T, Tiedt S, Groiß V et al. Dual PI3K/ mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia. Leukemia. 2015;29(4):828–38
  • 31. Kohn AD, Summers SA, Birnbaum MJ, Roth RA. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem. 1996;271(49):31372–8.
  • 32. Blackburn JS, Liu S, Wilder JL, Dobrinski KP, Lobbardi R, Moore FE et al. Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation. Cancer Cell. 2014;25(3):366–78.
  • 33. Küçükcankurt F, Erbilgin Y, Fırtına S, Ng ÖH, Karakaş Z, Çelkan T, et al. PTEN and AKT1 variations in childhood T-cell acute lymphoblastic leukemia. Turk J Hematol. 2020;37(2):98-103.
  • 34. Naderali E, Valipour B, Khaki AA, Rad JS, Alihemmati A, Rahmati M, et al. Positive effects of PI3K/Akt signaling inhibition on PTEN and P53 in prevention of acute lymphoblastic leukemia tumor cells. Adv Pharm Bull. 2019; 9(3):470-80.
  • 35. Chan CH, Jo U, Kohrman A, Rezaeian AH, Chou PC, Logothetis C, et al. Posttranslational regulation of Akt in human cancer. Cell Biosci. 2014;4(1):59.
  • 36. Piovan E, Yu J, Tosello V, Herranz D, Ambesi- Impiombato A, DaSilva AC et al. Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. Cancer Cell. 2013;24(6):766–76.
  • 37. Mao Z, Zhou J, Luan J, Sheng W, Shen X, Dong X. Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/ Akt signaling pathway in ER-negative human gastric cancer cells. Biomed Pharmacother. 2013;68(2):179–83.
  • 38. Neri LM, Cani A, Martelli AM, Simioni C, Junghanss C, Tabellini G et al. Targeting the PI3K/ Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. Leukemia. 2014;28(4):739–48.
  • 39. Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A et al. Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. J Clin Oncol. 2015 Sep 20;33(27):2938–48.
  • 40. Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013; 381(9881):1943-55.
  • 41. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13(10):1203– 10
  • 42. Morishita N, Tsukahara H, Chayama K, Ishida T, Washio K, Miyamura T, et al. Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2012;59(1):83-9.

PTEN and AKT1 Gene Expression Levels in Childhood T-ALL Patients

Yıl 2020, Cilt: 3 Sayı: 3, 114 - 121, 05.11.2020

Öz

Objective: Impaired activation of the PI3K/AKT signaling pathway has been associated with tumor development. The PTEN/AKT pathway plays a critical role in cell growth and survival and has been associated with chemotherapy resistance in leukemia. In this study, PTEN and AKT1 gene expression were determined in childhood T-ALL patients, and the effect was investigated on the prognosis of the disease. Materials and Methods: Bone marrow samples from 39 childhood cases were obtained at the time of diagnosis and screened with real-time quantitative PCR for PTEN and AKT1 genes. Results: In our study, no difference between T-ALL patients compared to controls was observed in PTEN gene expression whereas AKT1 gene expression was significantly increased (p<0.0001). There was no significant relationship between gene expression and clinical features of the patients, overall and disease-free survival rates while induction therapy-related survival analyzes revealed a significant relationship between PTEN and AKT1 gene expression and overall survival rates (p=0.026 and p=0.034 Cox regression analysis, respectively). Conclusion: In our study, the presence of increased AKT1 gene expression was demonstrated in T-ALL patients independent of PTEN expression. Future studies will reveal whether it will be a suitable candidate for targeted therapies.

Proje Numarası

BAP Proje No: 48185 ve İstanbul Kalkınma Ajansı Proje No: TR10/15/YNK/0093

Kaynakça

  • 1. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49:1211–8.
  • 2. Ferrando A. Can one target T-cell ALL? Best Pract Rese. Clin Haematol. 2018;31(4);361–6.
  • 3. Okumura N, Yoshida H, Kitagishi Y, Murakami M, Nishimura Y, Matsuda S. PI3K/AKT/PTEN signaling as a molecular target in leukemia angiogenesis. Advances in Hematology. 2012.
  • 4. Mayer IA, Arteaga CL. The PI3K/AKT Pathway as a Target for Cancer Treatment. Annu Rev Med. 2016;67:11–28.
  • 5. Worby CA, Dixon JE. PTEN. Annu Rev Biochem. 2014; 83(1):641–69.
  • 6. Milella M, Falcone I, Conciatori F, Cesta Incani U, Del Curatolo A, Inzerilli N et al. PTEN: Multiple functions in human malignant tumors. Front Oncol. 2015;16(5):24.
  • 7. Wickremasinghe RG, Prentice AG, Steele AJ. Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets. Br J Haematol. 2011;153(5):545–56.
  • 8. Shi Y, Paluch BE, Wang X, Jiang X. PTEN at a glance. J Cell Sci. 2012;125(20):4687–92.
  • 9. Chalhoub N, Baker SJ. PTEN and the PI3- kinase pathway in cancer. Annu Rev Pathol. 2009;4:127–50.
  • 10. Kharas GM, Okabe R, JJ. Ganis, Gozo M, Khandan T, Paktinat M, Gilliland GD et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood. 2010;115(7):1406–15.
  • 11. Cai J, Xu L, Tang H, Yang Q, Yi X, Fang Y et al. The Role of the PTEN/PI3K/Akt Pathway on Prognosis in Epithelial Ovarian Cancer: A Meta- Analysis. Oncologist. 2014;19(5):528–35.
  • 12. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira S-M, Garcia-Echeverria C et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci. 2009;106(1):268–73.
  • 13. Panuzzo C, Crivellaro S, Carrà G, Guerrasio A, Saglio G, Morotti A. BCR-ABL promotes PTEN downregulation in chronic myeloid leukemia. PloS One. 2014;9(10):e110682.
  • 14. Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM et al. Mutation of Pten/ Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A. 1999;96(4):1563–8.
  • 15. Philip C-A, Laskov I, Beauchamp M-C, Marques M, Amin O, Bitharas J et al. Inhibition of PI3KAKT- mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. BMC Cancer. 2017;17(1):638.
  • 16. Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, Bose S. PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer. 2004;112(3):407–10.
  • 17. Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/ Akt pathway sustain primary T cell leukemia viability. J Clin Invest. 2008;118(11):3762–74.
  • 18. Mendes RD, Canté-Barrett K, Pieters R, Meijerink JPP. The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia. Haematologica. 2016;101(9):1010–7.
  • 19. Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD et al. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia. Haematologica. 2013;98(6):928–36.
  • 20. Paganin M, Grillo MF, Silvestri D, Scapinello G, Buldini B, Cazzaniga G et al. The presence of mutated and deleted PTEN is associated with an increased risk of relapse in childhood T cell acute lymphoblastic leukaemia treated with AIEOP-BFM ALL protocols. Br J Haematol. 2018;182(5):705–11.
  • 21. Weerkamp F, Baert MR, Naber BA, Koster EE, de Haas EF, Atkuri KR et al. Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules. Proc Natl Acad Sci U S A. 2006;103(9):3322-6.
  • 22. Ng OH, Erbilgin Y, Firtina S, Celkan T, Karakas Z, Aydogan G et al. Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia. Blood Cancer J. 2014;4(3):e192.
  • 23. Hoelzer D, Gökbuget N. Diagnostik und therapie der akuten lymphatischen leukämie des erwachsenen. Der Onkologe. 2002;8:672-85.
  • 24. Livak KJ, Schmittgen, TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4): 402–8.
  • 25. Hisamatsu Y, Oki E, Otsu H, Ando K, Saeki H, Tokunaga E et al. Effect of EGFR and p-AKT Overexpression on Chromosomal Instability in Gastric Cancer. Annals of Surgical Oncology. 2016;23:1986–92.
  • 26. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24(50):7455–64.
  • 27. Manning BD, Cantley LC. AKT/PKB Signaling: Navigating Downstream. Cell. 2007 Jun 29;129(7):1261–74.
  • 28. Knobbe CB, Reifenberger G. Genetic Alterations and Aberrant Expression of Genes Related to the Phosphatidyl-lnositol-3′-Kinase/ Protein Kinase B (Akt) Signal Transduction Pathway in Glioblastomas. Brain Pathology. 2006;13(4):507–18.
  • 29. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three akts. Genes Dev. 1999;13(22):2905–27.
  • 30. Sandhöfer N, Metzeler KH, Rothenberg M, Herold T, Tiedt S, Groiß V et al. Dual PI3K/ mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia. Leukemia. 2015;29(4):828–38
  • 31. Kohn AD, Summers SA, Birnbaum MJ, Roth RA. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem. 1996;271(49):31372–8.
  • 32. Blackburn JS, Liu S, Wilder JL, Dobrinski KP, Lobbardi R, Moore FE et al. Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation. Cancer Cell. 2014;25(3):366–78.
  • 33. Küçükcankurt F, Erbilgin Y, Fırtına S, Ng ÖH, Karakaş Z, Çelkan T, et al. PTEN and AKT1 variations in childhood T-cell acute lymphoblastic leukemia. Turk J Hematol. 2020;37(2):98-103.
  • 34. Naderali E, Valipour B, Khaki AA, Rad JS, Alihemmati A, Rahmati M, et al. Positive effects of PI3K/Akt signaling inhibition on PTEN and P53 in prevention of acute lymphoblastic leukemia tumor cells. Adv Pharm Bull. 2019; 9(3):470-80.
  • 35. Chan CH, Jo U, Kohrman A, Rezaeian AH, Chou PC, Logothetis C, et al. Posttranslational regulation of Akt in human cancer. Cell Biosci. 2014;4(1):59.
  • 36. Piovan E, Yu J, Tosello V, Herranz D, Ambesi- Impiombato A, DaSilva AC et al. Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. Cancer Cell. 2013;24(6):766–76.
  • 37. Mao Z, Zhou J, Luan J, Sheng W, Shen X, Dong X. Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/ Akt signaling pathway in ER-negative human gastric cancer cells. Biomed Pharmacother. 2013;68(2):179–83.
  • 38. Neri LM, Cani A, Martelli AM, Simioni C, Junghanss C, Tabellini G et al. Targeting the PI3K/ Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. Leukemia. 2014;28(4):739–48.
  • 39. Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A et al. Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. J Clin Oncol. 2015 Sep 20;33(27):2938–48.
  • 40. Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013; 381(9881):1943-55.
  • 41. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13(10):1203– 10
  • 42. Morishita N, Tsukahara H, Chayama K, Ishida T, Washio K, Miyamura T, et al. Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2012;59(1):83-9.
Toplam 42 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Klinik Tıp Bilimleri
Bölüm Research Article
Yazarlar

Fulya Küçükcankurt 0000-0002-5345-9072

Özden Hatırnaz Ng 0000-0001-7728-6527

Müge Sayitoğlu 0000-0002-8648-213X

Yücel Erbilgin 0000-0001-6969-6649

Proje Numarası BAP Proje No: 48185 ve İstanbul Kalkınma Ajansı Proje No: TR10/15/YNK/0093
Yayımlanma Tarihi 5 Kasım 2020
Gönderilme Tarihi 31 Ağustos 2020
Yayımlandığı Sayı Yıl 2020 Cilt: 3 Sayı: 3

Kaynak Göster

MLA Küçükcankurt, Fulya vd. “Çocukluk Çağı T-ALL Hastalarında PTEN Ve AKT1 Gen Anlatım Düzeyleri”. Sağlık Bilimlerinde İleri Araştırmalar Dergisi, c. 3, sy. 3, 2020, ss. 114-21.