HDAC2, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9 Gen İfade Seviyelerinin Çocukluk Çağı Akut Lösemilerinde Prognoz İle İlişkisi

Year 2018, , 400 - 406, 01.12.2018

Dilara Akın Balı Ahmet Emin Kürekçi Mehmet Nejat Akar

https://doi.org/10.17343/sdutfd.373907

Abstract

Amaç: Histon deasetilazların değişmiş ifadesi hematolojik
maligniteler için kanser tedavisinde hedef olabilecek niteliktedir. HDAC
mutasyonları ve anormal ifade seviyeleri çeşitli kanser tiplerinde ve özellikle
hematolojik malignitelerde sıklıkla görülmekte olduğu, çocukluk çağı lösemi
örneklerinde HDAC2, HDAC3, HDAC6, HDAC7 ve HDAC8 gen ifadelerinin sağlıklı
çocuk kemik iliği örneklerine göre önemli derece yüksek olduğu rapor
edilmiştir.

Gereç ve
Yöntem: Çalışmamızda 6 HDAC geninin gen
ifade profilini çocukluk çağı akut lösemisinde kantitatif Real Time PCR yöntemi
kullanılması ile tedavinin farklı zamanlarında belirlenmesi gerçekleştirilmiştir.

Bulgular: Çalışmamız sonucunda çocukluk çağı lösemi örneklerinde
HDAC genleri ifade seviyelerinin birbirine göre farklılık gösterdiği
gözlenmiştir. Çalışmamızda; tedavi öncesinde, kontrol örneklerinin ifadelenme
seviyelerine göre; HDAC2 ve HDAC9 ifadelenme seviyelerinin düşük, HDAC 4 ve
HDAC 8 eşit seviyede ve son olarak HDAC 5 ve HDAC7 yüksek olduğu
belirlenmiştir. Tedavi sonrasında ise, 
kontrol örneklerinin ifadelenme seviyelerine göre; HDAC2 ve HDAC9
ifadelenme seviyelerinin düşük, HDAC 4 ve HDAC 8 yükseldiği ve HDAC 5 ve HDAC7’nin
ise düştüğü tespit edilmiştir.

Sonuçlar: Tümor
gelişiminde rol oynayan genlerin ve/veya yolakları kontrol eden HDAC gen
seviyelerinin artması, tedavi sonrasında ise bu ifadelenme seviyelerinin sağlıklı
örneklerin seviyesine eşit olması, HDAC genlerinin kanser patogenezi ile direkt
ilişkide olabileceğini düşündürmektedir.

Keywords

Histondeasetilaz, lösemi, gen ifadesi

HDAC2, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9 Gene Expression Levels Associated with Prognosis in Childhood Acute Leukemia

Abstract

Objective: HDAC have been frequently observed in several types of cancers, including haematological malignancies. Altered expression of HDACs and mutations are common feature in several human malignancies and may represent an interesting target for cancer treatment, including haematological malignancies. HDAC2, HDAC3, HDAC6, HDAC7 and HDAC8 gene expressions in childhood leukemia cases were reported to be significantly higher than in healthy pediatric bone marrow samples. This study aims evaluting the gene expressions of HDACs in different types of childhood leukemia. Material and Methods: In our study, identification and comparation with reference gene of 6 HDAC genes were performed at before and after treatment in 13 patients with acute childhood leukemia samples using quantitative Real-Time PCR Results: As a result of our study, it was observed that expression levels of HDAC genes in childhood leukemia were different according to each other. In our study; according to the level of expression of patients samples to control samples before treatment; HDAC2 and HDAC9 expression levels are low, HDAC 4 and HDAC 8 are equal, and finally HDAC 5 and HDAC7 are high. After treatment, according to the expression levels of patients samples to control samples; It has been found that HDAC2 and HDAC9 rendering levels are low, HDAC 4 and HDAC 8 are rising, and HDAC 5 and HDAC 7 are falling. Conclusions: The elevation of HDAC gene levels controlling genes and / or pathways involved in tumor development and the equivalence of these expression levels to that of healthy specimens after treatment suggests that HDAC genes may be directly related to cancer pathogenesis. 

Keywords

Histone deacetylases, leukemia, gene expression, epigenetic mechanism

References

• 1. Verdin E, Dequiedt F, Kasler HG. Class II histone deacetylases: versatile regulators. Trends in Genetics 2003; 19: 286–293.
• 2. Melnick A, Licht JD. Histone deacetylases as therapeutic targets in hematologic malignancies. Curr Opin Hematol 2002;9(4):322-32.
• 3.Moreno DA, Scrideli CA, Cortez MA, de Paula Queiroz R, Valera ET, da Silva Silveira V, et al. Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. Br J Haematol 2010;150(6):665-73.
• 4. Klimek VM, Fircanis S, Maslak P, Guernah I, Baum M, Wu N, Panageas K, et al. Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clinical Cancer Research 2008: 14; 826–832.
• 5. Altucci L, Minucci S. Epigenetic therapies in haematological malignancies: searching for true targets. European Journal of Cancer 2009:45;1137–1145.
• 6. Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. Journal of Cellular Physiology 2000: 184; 1–16.
• 7. Mullighan CG, Downing JR. Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions. Leukemia 2009:23(7):1209-18.
• 8. Roberts KG, Mullighan CG. Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nature reviews Clinical oncology 2015: 12(6):344-57.
• 9. Kuiper RP, Schoenmakers EF, van Reijmersdal SV, et al. High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 2007:21(6):1258-66.
• 10. Apak H. Çocukluk çağı lösemileri. Türk Pediatri Arşivi. 2006;41:189-96.
• 11. Kim DH, Kim M, Kwon HJ. Histone deacetylase in carcinogenesis and its inhibitors as anti-cancer agents. Journal of Biochemistry and Molecular Biology 2003: 36; 110–119.
• 12.Witt O, Deubzer HE, Milde T, Oehme I.HDAC family: what are the cancer relevant targets? Cancer Letters 2009: 277; 8–21.
• 13. Lam YM, Chan YF, Chan LC, Ng RK. Histone deacetylase inhibitors induce leukemia gene expression in cord blood hematopoietic stem cells expanded ex vivo.Int J Hematol 2017: 105(1):37-43.
• 14. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nature Reviews Cancer 2001: 1;194–202.
• 15. Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, Craddock C, Turner BM. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 2005: 19: 1751–1759.
• 16. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell 2007: 128; 669–681.