Lösemi patogenezinde miRNA 15a/16–1 lokus delesyonlarının ve Protein L-isoaspartate O-methyltransferase (PCMT1) enziminin rolü

Kanser, ülkemizde ve dünyada sıklıkla görülen hastalıklardan birisidir. Karsinojenez sırasında büyük değişimlere uğrayan hücresel gen ifadesi profili DNA dizisi dışında DNA metilasyonu, kodlanmayan RNA’lar (ncRNA), RNA interferansı (RNAi), histon varyantları ve post-translasyonel histon modifikasyonları gibi başkaca epigenetik mekanizmalar tarafından da kontrol edilebilmektedir. Bununla birlikte; mutasyonlar, delesyonlar ve translokasyonlar gibi çeşitli sebepler sonucu ortaya çıkan genetik anomaliler kanser oluşumunda ve tedaviye verilen yanıtta önemli rol oynamakta ve klinikte, kanser alt tiplerinin belirlenmesinde incelenmektedir. 13. kromozomun q kolunda bulunan miRNA 15a/16-1 lokusu delesyonlarının Mcl1, Bcl2, Ets1, Jun gibi kanser ile ilişkili birçok geni etkilediği gösterilmiştir. Ayrıca, bu miRNA’ların regüle ettiği Protein L-isoaspartate O-methyltransferase (PCMT1) proteinin apoptoz yolağı üzerindeki etkisi dolayısıyla karsinojenez üzerinde önemli rol oynadığı birçok çalışma ile vurgulanmıştır. Literatürde miRNA 15a/16-1 lokusu ve p53 arasında hücre proliferasyonu ve büyümesini sağlayan sinyallerin üretimini düzenleyen bir feedback döngüsünün varlığı tartışılmaktadır. Yapılan çalışmalar, miRNA 15a/16-1 lokusunu tümör baskılayıcı gen bölgesi, PCMT1’i ise onkogen olarak tanımlamaktadır. Buna paralel olarak, miRNA 15a/16-1 lokusunu da içeren 13q14.3 bölgesi delesyonu birçok lenfoid ve miyeloid lösemi alt türlerinde tespit edilmiş olup, klinikte rutin taramalara dahil edilme potansiyeline sahiptir. Lösemi hastalarında 13q14.3 bölgesi delesyonunun araştırılması hastalığın alt tiplerinin sınıflandırılmasını ve hatta uygulanacak tedavi rejimini yönlendirebilecek önemli sonuçlar elde edilmesini sağlayabilecektir.

Anahtar Kelimeler:

Epigenetik, lösemi, apoptoz, miRNA 15a/16–1, delesyon, PCMT1

A new perspective on carcinogenesis: miRNA 15a/16–1 cluster deletions promote cell survival via Protein L-isoaspartate O-methyltransferase (PCMT1) activity

Cancer is a commonly encountered disease both in Turkey and worldwide. Cellular gene expression profiles that drastically change during carcinogenesis can be regulated via several epigenetic mechanisms such as DNA methylation, non-coding RNAs (ncRNA), RNA interference (RNAi), histone variants and post-translational modifications of histones. In addition to these mechanisms, genetic anomalies that arise due to various reasons including mutations, deletions and translocations have significant roles both in carcinogenesis and the response to treatment and are screened routinely in clinic when determining cancer subtypes. miRNA 15a/16-1 cluster which is located on the q arm of chromosome 13 is often deleted in cancers and regulates the activity of several cancer-associated genes such as Mcl1, Bcl2, Ets1, Jun. Furthermore, the role of Protein L-isoaspartate O-methyltransferase (PCMT1) which is regulated by these miRNAs, in carcinogenesis through its effects in apoptosis pathway is emphasized by various studies. It is suggested that there is a feedback loop between miRNA 15a/16-1 cluster and p53 which regulates cellular signals for proliferation and cell survival. Studies describe miRNA 15a/16-1 cluster as a tumor suppressor, while identifying PCMT1 as an oncogene. In line with this, deletions in the 13q14.3 region which also spans the miRNA 15a/16-1 cluster are detected in multiple lymphoid and myeloid leukemia subtypes and have the potential to be included in routine clinical genetic screens. Examining 13q14.3 deletions in leukemia patients has the potential to yield important results that could be useful both in determining cancer subtypes and deciding which therapeutic regime to apply on a single-patient basis.

Keywords:

Epigenetics, leukemia, apoptosis, miRNA 15a/16–1, deletion, PCMT1,

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