Turkiye Klinikleri Journal of Medical Sciences

.: ORIGINAL RESEARCH
Akut Miyeloid Lösemi Hastalarında 'Peroksizom Proliferatör Aktive Edici Reseptör-Gama' Geninin Epigenetik Düzenlenmesi
Epigenetic Regulation of the 'Peroxisome Proliferator Actived Receptor-Gamma' Gene in Acute Myeloid Leukemia Patients
Deniz GÖREN ŞAHINa, Eren GÜNDÜZb, Buket YURTERİc, Ahmet YEŞİLYURTc, Neslihan ANDIÇb, Hava ÜSKÜDAR TEKEb, Olga Meltem AKAYd
aHematoloji BD, Demiroğlu Bilim Üniversitesi Tıp Fakültesi, İstanbul, TÜRKİYE
bHematoloji BD, Eskişehir Osmangazi Üniversitesi Tıp Fakültesi, Eskişehir, TÜRKİYE
cTıbbi Genetik Kliniği, Ankara Dışkapı Yıldırım Beyazıt Eğitim ve Araştırma Hastanesi, Ankara, TÜRKİYE
dHematoloji BD, Koç Üniversitesi Tıp Fakültesi, İstanbul, TÜRKİYE
Turkiye Klinikleri J Med Sci. 2019;39(4):375-80
doi: 10.5336/medsci.2019-66573
Article Language: TR
Full Text
ÖZET
 Amaç: Peroksizom proliferatör aktive edici reseptör (PPAR) gama; hücresel büyüme, farklılaşma ve apopitozisi düzenleyen nükleer hormon reseptör ailesinin bir üyesidir. Normal kemik iliğinde ve periferik CD34+ hücrelerde PPAR gama ifadesi mevcuttur. Akut miyeloid lösemi (AML)'de bu ifadenin azaldığını gösteren çalışmalar vardır. Ancak, bu azalmanın transkripsiyonel mi yoksa epigenetik mi olduğuna dair çalışma yoktur. Hipotezimiz, AML hastalarında PPAR gama ifadesinin azalmasının, bu gen bölgesinin aşırı metilasyonu sonucu olduğudur. Bu amaca yönelik olarak çalışmamızda, AML ve sağlıklı kontrol grubunda PPAR gama geninin ifadesi ve metilasyon düzeylerini araştırdık. Gereç veYöntemler: Çalışmaya yeni tanı konulmuş 31 AML hastası, 25 sağlıklı birey dâhil edildi. PPAR gama gen ifadesinin farklılığına gerçek zamanlı polimeraz zincir reaksiyonu (RT-PCR) tekniği ile bakıldı. Aynı hastalarda Epitect bisülfit protokolü uygulanarak metilasyon spesifik PCR yapıldı. PPAR gama gen bölgesinde aşırı metilasyon olabilecek promoter bölgesine uygun primerler dizayn edildi. Ardından termal cycler ile bisülfit DNA dönüşümü yapıldı. Epitect HRM PCR protokülü ile PPAR gama genindeki metilasyon düzeyi ölçüldü. Bulgular: RT-PCR sonucunda AML hastalarında PPAR gama gen ifadesinin sağlıklı bireylere göre yaklaşık 1,5 kat kadar azaldığı tespit edildi. PPAR gama ifadesinin azaldığı gösterilen hastalarda metilasyon spesifik PCR ile PPAR gama geni promoter bölgesinin metilasyon durumu incelendiğinde, AML hastalarında aday gen bölgesinde metilasyonun anlamlı olarak arttığı (AML hastalarında %29 ve kontrol grubunda %8, p<0,001) tespit edildi. Sonuç: Çalışmamızda, kemik iliğindeki hematopoetik süreci düzenleyen genlerden biri olan PPAR gama geninin ifadesinin AML hastalarında anlamlı olarak azaldığı izlenmiştir. Bunun yanı sıra, bu gen ifadesinin baskılanmasından, genin promoter bölgesinin aşırı metilasyonunun sorumlu olabileceği gösterilmiştir.

Anahtar Kelimeler: Akut miyeloid lösemi; epigenetik; peroksizom aktive edici reseptör gama
ABSTRACT
 Objective: Peroxisome proliferator activated receptor gamma (PPAR) is a member of the nuclear hormone receptor family that regulates cellular growth, differentiation and apoptosis. PPAR gamma expression is present in normal bone marrow and peripheral CD34+ cells. There are studies showing that this regulation is decreased in acute myeloblastic leukemia (AML). However, there is no study of whether this reduction is transcriptional or epigenetic. For this purpose we investigated the expression and methylation levels of the PPAR gamma gene in AML and healthy control group. Material and Methods: Thirty-one newly diagnosed cases of AML and 25 healthy individuals were included in the study. Differences in the PPAR gamma gene expression between the study group and the control group were analyzed by real time polymerase chain reaction (RT-PCR) technique. Methylation-specific PCR was performed using the Epitect bisulfite protocol. After primers were designed, bisulfite DNA transformation was performed. The methylation level of the PPAR gamma gene was measured by the Epitect HRM PCR protocol. Results: As a result of RT-PCR, the expression of PPAR gamma gene in AML cases was found to be reduced by about 1.5 times compared to healthy individuals. When the methylation status of the PPAR gamma promoter region was examined by methylation-specific PCR in the cases where the PPAR gamma expression was decreased, methylation in the candidate gene region in AML cases was significantly increased (29% in AML cases and 8% in control group, p<0.001). Conclusion: In our study, the expression of the PPAR gamma gene was significantly reduced in patients with AML. It has also been shown that over-methylation of the promoter region may be responsible for suppression of this gene expression.

Keywords: Acute myeloid leukemia; epigenetic; peroxisome proliferator activated receptor gamma
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