Publication: Akut miyeloid löseminin transkriptom bazlı moleküler alt tiplemesi ve farklıterapötik ajanlar altında moleküler cevapların aydınlatılması
Abstract
AKUT MİYELOİD LÖSEMİNİN TRANSKRİPTOM BAZLI MOLEKÜLER ALT TİPLEMESİ VE FARKLI TERAPÖTİK AJANLAR ALTINDA MOLEKÜLER CEVAPLARIN AYDINLATILMASI Akut miyeloid lösemi (AML), kanda ve kemik iliğinde biriken ve normal kan hücrelerine müdahale eden anormal hücrelerin hızlı büyümesiyle ortaya çıkan, bir tür habis ve heterojen hematopoetik sistem hastalığıdır. Bugüne kadar, AML'nin ilk olarak uygulanan tedavisi hala geleneksel kemoterapi rejimine dayanmaktadır. Bununla birlikte, AML'nin remisyon oranının tamamı, özellikle yaşlı hastalarda hala iyi bir durum sergilememekte ve tam remisyondan sonra nüks oranı hala yüksektir.. Son birkaç yıl içerisinde AML'nin anlaşılmasında ve tedavisinde büyük gelişmeler kaydedilmesine rağmen, AML hastalarının hayatta kalmalarını uzatacak çok az ilerleme kaydedilmiştir. Bunlara ek olarak, son on yıldaki gen ekspresyonu profilleme çalışmaları AML hakkında önemli moleküler bulgular ortaya koymuştur, ancak yeterli tarama ve etkili tedavi stratejileri henüz uygun bir şekilde başarılamamıştır. Bu çalışmada yetişkin AML hastalarının transkriptom verileri üzerinde bir meta-analiz yapılması ve genom ölçeğinde biyo-moleküler ağlara sahip ekspresyon profilleri tarafından RNA, protein ve metabolit seviyelerinde reporter genlerin belirlenmesi hedeflenmektedir. Bu yaklaşım, AML'deki halihazırda bilinen biyobelirteçleri, tümör baskılayıcıları ve onkogenleri, ayrıca yeni biyobelirteç adayları ve potansiyel terapötik hedefler olarak miRNA'ları, transkripsiyon faktörlerini, diğer ve metabolitleri ortaya çıkarmıştır. Prognostik biyobelirteçlere ek olarak, AML tedavisi için potansiyel terapötik adayları önceliklendirmek için ilaç yeniden konumlandırma yapılmıştır. Nortriptilin, doksepin ve estramustinin AML hücre dizileri üzerindeki inhibitör etkileri, bu ilaçların AML tedavisinde kullanıldığı ileri çalışmalar için umut verici çıktılar sağlamıştır. Bu çalışma prognostik biyobelirteçlerde ilacın yeniden konumlandırılması yoluyla yeni hastalık adaylarının tespit edilmesini ve hastalık teşhisinde iyileşmeyi sağlayacak gelecekteki çalışmalar için yeni bir sistem sağlar. Tekrarlayan mutasyona uğramış AML genleri ve yolakları arasındaki potansiyel önemli birçok ilişkinin tanınması, patogenezin genetik kurallarının anlaşılması için kapsamlı bir temel oluşturacaktır.
TRANSCRIPTOME BASED MOLECULAR SUBTYPING OF AML AND ELUCIDATION OF MOLECULAR RESPONSES UNDER DIFFERENT THERAPEUTIC AGENTS Acute myeloid leukemia (AML) is a malignant and heterogeneous disease of the hematopoietic system characterized by rapid growth of abnormal cells that accumulate in the blood and bone marrow and interfere with blood cells. To date, first-line treatment of AML has been based mostly on conventional chemotherapy. However, the rate of complete remission of AML is still not optimistic, especially in elderly patients, and the relapse rate after complete remission is still high. Despite significant improvements in the understanding and treatment of AML in recent years, little progress has been made in AML patient outcomes and survival. In addition, gene expression profiling studies have provided molecular insights into AML over the past decade, but adequate screening and effective treatment strategies have yet to be developed. In the current study, we aim to perform a meta-analysis of transcriptome data of adult AML patients and identify reporter biomolecules at the RNA, protein, and metabolite levels by integrating gene expression profiles with genome-level biomolecular networks. This approach revealed already known biomarkers, tumor suppressors and oncogenes in AML, as well as miRNAs, transcription factors, others and metabolites as novel biomarker candidates and potential therapeutic targets. In addition to prognostic biomarkers, we performed drug repositioning to prioritize potential therapeutic candidates for the treatment of AML.As a result of these analyzes, we proposed repositioned drugs including desipramine, doxepin, estramustine, hydrochlorothiazide, nortriptyline, and risedronate for the drug treatment of AML. The inhibitory effects of the nortriptyline, doxepin and estramustine on AML cell lines gave us promising output for further studies using these drugs in the treatment of AML. This study provides a framework for future studies that will improve disease diagnostics and enable the identification of new drug candidates by repositioning drugs on prognostic biomarkers. The recognition of many potentially important relationships between recurrent mutant AML genes and pathways provides a comprehensive foundation for understanding the genetic rules of pathogenesis.
TRANSCRIPTOME BASED MOLECULAR SUBTYPING OF AML AND ELUCIDATION OF MOLECULAR RESPONSES UNDER DIFFERENT THERAPEUTIC AGENTS Acute myeloid leukemia (AML) is a malignant and heterogeneous disease of the hematopoietic system characterized by rapid growth of abnormal cells that accumulate in the blood and bone marrow and interfere with blood cells. To date, first-line treatment of AML has been based mostly on conventional chemotherapy. However, the rate of complete remission of AML is still not optimistic, especially in elderly patients, and the relapse rate after complete remission is still high. Despite significant improvements in the understanding and treatment of AML in recent years, little progress has been made in AML patient outcomes and survival. In addition, gene expression profiling studies have provided molecular insights into AML over the past decade, but adequate screening and effective treatment strategies have yet to be developed. In the current study, we aim to perform a meta-analysis of transcriptome data of adult AML patients and identify reporter biomolecules at the RNA, protein, and metabolite levels by integrating gene expression profiles with genome-level biomolecular networks. This approach revealed already known biomarkers, tumor suppressors and oncogenes in AML, as well as miRNAs, transcription factors, others and metabolites as novel biomarker candidates and potential therapeutic targets. In addition to prognostic biomarkers, we performed drug repositioning to prioritize potential therapeutic candidates for the treatment of AML.As a result of these analyzes, we proposed repositioned drugs including desipramine, doxepin, estramustine, hydrochlorothiazide, nortriptyline, and risedronate for the drug treatment of AML. The inhibitory effects of the nortriptyline, doxepin and estramustine on AML cell lines gave us promising output for further studies using these drugs in the treatment of AML. This study provides a framework for future studies that will improve disease diagnostics and enable the identification of new drug candidates by repositioning drugs on prognostic biomarkers. The recognition of many potentially important relationships between recurrent mutant AML genes and pathways provides a comprehensive foundation for understanding the genetic rules of pathogenesis.