Tirozin kinaz ınhibitörlerine duyarlı ve dirençli kronik myeloid lösemi hastalarında, uzun kodlamayan RNA ekspresyonlarının moleküler düzeyde araştırılması
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Dosyalar
Tarih
2018
Yazarlar
Dergi Başlığı
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Yayıncı
Ege Üniversitesi, Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Uzun kodlamayan RNA' lar (lncRNA), ortalama 200-100 kbp uzunluğunda, hücrelerde gen ifadesinin epigenetik düzeyde kontrolünden sorumlu olan RNA molekülleridir. LncRNA' ların ekspresyon düzensizliği çeşitli insan kanser tipleri ile ilişkilidir. Ancak, Kronik myeloid lösemi' de (KML) ve özellikle tirozin kinaz inhibitörlerine karşı oluşan dirençte lncRNA' ların fonksiyonları tam olarak bilinmemektedir. Uzun kodlamayan RNA NEAT1 çeşitli kanser türlerinde önemli role sahip olup, iki kısa izoforma sahiptir: kısa form NEAT1_1 ve uzun form NEAT1_2. NEAT1 aynı zamanda nukleusta sub bodies olan 'paraspeckles' ve microspeckles oluşumundan da sorumludur. Bu çalışmanın amacı KML'de ve tirozin kinaz inhibitörlerine karşı gelişen direnç mekanizmasında etki gösteren lncRNA ekspresyon profillerinin belirlenmesi ve belirlenen lncRNA'ların TKİ direnç mekanizmasında ve KML progresyonundaki rollerinin saptanmasıdır. Dolayısıyla KML'de gen ifadesini direkt veya dolaylı şekilde etkileyen lncRNA' ların profillenmesi, sağlıklı olgulardan ve tirozin kinaz inhibitörlerine duyarlı/dirençli kronik myeloid lösemi hastalarından elde edilen kan örneklerinden RNAeasy Mini kit (Qiagen) ile total RNA izolasyonu, 'Thermocycler' cihazında qRT-PCR (kantitatif revers transkriptaz-gerçek zamanlı polimeraz zincir reaksiyonu) yöntemi ile cDNA (komplemanter DNA) sentezi ve 'ABI 7500 Fast' cihazında qRT-PCR (gerçek zamanlı polimeraz zincir reaksiyonu) array ile yapılmıştır. Farklı ekspresyon seviyeleri gösteren lncRNA'lar potansiyel terapötik hedefler olabileceğinden, lncRNA' ları hedefleyen tedavi stratejisinin tirozin kinaz inhibitörlerine karşı direnç gösteren KML hastalarının tedavisi için de, umut verici nitelikte olacağını düşünmekteyiz.
Long non-coding RNAs (lncRNAs) are non-coding RNAs that are > 200nt, and many have been found to be involved in many epigenetic mechanisms such as chromatin modification, genomic imprinting, and regulation of gene expression. Deregulated expression of Nuclear paraspeckle assembly transcript 1 (NEAT1) has been found to be related with the progression of several cancers. The expression of NEAT1 normally results in the production of a class of nuclear RNA-protein complex named 'paraspeckles' in mammalian nucleus. The function of NEAT1 and 'paraspeckles' in the BCR-ABL associated pathways (AKT, ERK, STAT pathways) in KML still remains largely unknown, but recent studies showed NEAT1 overexpression in leukemia cell line reduced MDR (multi drug resistance) induced pathways in KML. In this study we aimed to investigate the role of lncRNA NEAT1 in BCR-ABL mediated tumorigenesis in CML. We hypothesize that NEAT1 might target imatinib resistance-associated genes and downstream of the BCR-ABL fusion protein genes (PI3K / Akt, mTOR, JAK-STAT) in CML. For this reason, our study may contribute to an elucidation of imatinib response and imatinib resistance mechanisms in association with NEAT1 and 'paraspeckles' in CML.Furthermore, since BCR/ABL was found to translocate from the cytoplasm to the nucleus following genotoxic stress, and then associates with ATR-dependent DNA damage response pathways, which is also found to be regulated by 'paraspeckles' and NEAT1 expression, it becomes intriguing to test if NEAT1 might be a novel target for the treatment of chronic myeloid leukemia.
Long non-coding RNAs (lncRNAs) are non-coding RNAs that are > 200nt, and many have been found to be involved in many epigenetic mechanisms such as chromatin modification, genomic imprinting, and regulation of gene expression. Deregulated expression of Nuclear paraspeckle assembly transcript 1 (NEAT1) has been found to be related with the progression of several cancers. The expression of NEAT1 normally results in the production of a class of nuclear RNA-protein complex named 'paraspeckles' in mammalian nucleus. The function of NEAT1 and 'paraspeckles' in the BCR-ABL associated pathways (AKT, ERK, STAT pathways) in KML still remains largely unknown, but recent studies showed NEAT1 overexpression in leukemia cell line reduced MDR (multi drug resistance) induced pathways in KML. In this study we aimed to investigate the role of lncRNA NEAT1 in BCR-ABL mediated tumorigenesis in CML. We hypothesize that NEAT1 might target imatinib resistance-associated genes and downstream of the BCR-ABL fusion protein genes (PI3K / Akt, mTOR, JAK-STAT) in CML. For this reason, our study may contribute to an elucidation of imatinib response and imatinib resistance mechanisms in association with NEAT1 and 'paraspeckles' in CML.Furthermore, since BCR/ABL was found to translocate from the cytoplasm to the nucleus following genotoxic stress, and then associates with ATR-dependent DNA damage response pathways, which is also found to be regulated by 'paraspeckles' and NEAT1 expression, it becomes intriguing to test if NEAT1 might be a novel target for the treatment of chronic myeloid leukemia.
Açıklama
Anahtar Kelimeler
KML, LncRNA, Tirozin Kinaz Inhibitörlerine Direnç, Chronic Myeloid Leukemia, Long Non-Coding RNAs, Resistance Mechanism of Tyrosine Kinase Inhibitor in CML
