o:5396 Molekularni mehanizmi patogeneze mijeloproliferativnih neoplazija : poremećaj ekspresije gena uključenih u proliferaciju i apoptozu doktorska disertacija Molecular mechanisms of pathogenesis of myeloproliferative neoplasms: deregulation of genes involved in cell proliferation and apoptosis : doctoral dissertation sr Mijeloproliferativne neoplazije (MPN) su hronični hematološki maligniteti koji se odlikuju autonomnom proliferacijom opredeljenih progenitora hematopoeze i aberantnom aktivacijom tirozin kinaznih signalnih puteva u kombinaciji sa snažnim odgovorom na citokine i faktore rasta. Tri bolesti predstavljaju MPN u užem smislu: policitemija vera (PV), esencijalna trombocitemija (ET) i mijelofibroza (MF). Jedna od komplikacija ovih oboljenja je njihova kasna evolucija u akutnu mijeloidnu leukemiju (AML). Važno obeležje ovih bolesti ja prisustvo „missense“ JAK2-V617F mutacije u sve tri bolesti, a procenat zastupljenosti mutacije po bolestima je različit. TakoĎe pokazano je da kod ovih pacijenata postoji tzv. efekat “doze gena”, odnosno da različit nivo V617F alela utiče kliničku sliku bolesti. JAK2-V617F mutacija dogaĎa se u 80% slučajeva na specifičnom haplotipu koji je nazvan 46/1 haplotip. Na koji način ovaj niz SNP-ova, koji se nalaze u JAK2 genu, predisponira nastajanje mutacije kao i njen uticaj na fenotip MPN, još nije utvrĎeno. Jedan od mogućih mehanizama je uticaj ovog haplotipa na transkripciju. Posebnu pažnju u okviru 46/1 haplotipa je privukao SNP rs12343867, koji u potpunosti asocira sa MPN. Proces apoptoze je deregulisan u hematološkim malignitetima, što dovodi do rezistencije malignih ćelija na signale smrti i obezbeĎuje im duži život u odnosu na normalne ćelije. Proces apoptoze nije detaljno izučen kod MPN, mada se zna da je direktno pogoĎen JAK2-V617F mutacijom. Naime, glavni signalni put preko STAT5 (Signal Transducers and Activators of Transcription) proteina direktno aktivira anti- apoptotski BCL2-xL protein, čime se smanjuje apoptoza. Deregulacija ostalih apoptotskih puteva u MPN nije u potpunosti rasvetljena Myeloproliferative neoplasms (MPN) are chronic hematological malignancies that are characterized by autonomous proliferation of committed hematopoietic progenitors and aberrant activation of tyrosine kinase signaling pathways, in combination with a strong response to cytokines and growth factors. Three major entities constitute MPN: polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). One of the complications of these diseases is their late evolution into acute myeloid leukemia. Important feature of these diseases is the presence of missense mutation JAK2- V617F and its variable representation among MPN entities. It is also shown that there is socalled effect of "gene dosage" in these patients, meaning that a different level of V617F alleles influences the clinical picture of the disorders. JAK2-V617F mutation occurs in 80% of cases on a specific haplotype, called 46/1 haplotype. Exact mechanism of action of this set of SNPs, that are located within the JAK2 gene, has not been determined yet. One of the possible mechanisms could be that it effects transcription. Among eight SNPs, included in this haplotype, SNP rs12343867 has drawn special attention because of its strong association with the MPN. The process of apoptosis is deregulated in hematological malignancies, leading to resistance of cancer cells to death signals, thus providing them a longer life span compared to normal cells. The process of apoptosis has not been extensively studied in MPN, although it is known that it is directly affected by the JAK2-V617F mutation. Specifically, the main signaling pathway through STAT5 protein directly activates anti-apoptotic BCL2- xL protein, thereby reducing apoptosis. Deregulation of other apoptotic pathways in MPN is not fully understood BIOLOGIJA - MOLEKULARNA BIOLOGIJA / BIOLOGY- MOLECULAR BIOLOGY Datum odbrane : 27.12.2012 Mijeloproliferativne neoplazije, JAK2-V617F mutacija, 46/1 haplotip, transkripciona regulacija, ekspresija JAK2 gena, apoptoza Myeloproliferative neoplasms, JAK2-V617F-mutation, 46/1 haplotype, transcriptional regulation, expression of the JAK2 gene, apoptosis 616-006.4: 576.352.5]: 577.218 (043.3) yes 1024559538 91552101 162 91552100 1024559538 2013-06-24T13:11:24.053Z 45 no 46 mentor Vesna M. Spasovski 2012 63 mentor Sonja Pavlović 2012 63 član komisije Sonja Pavlović 2012 63 mentor Dušanka Savić-Pavićević 2012 63 član komisije Dušanka Savić-Pavićević 2012 63 član komisije Gordana Nikčević 2012 PDF/A (132 lista) 3937445 http://phaidrabg.bg.ac.rs/o:5396 no yes 4 2013-06-24T13:11:24.320Z 70 11 1066841 1066867 BIOLOGIJA - MOLEKULARNA BIOLOGIJA / BIOLOGY- MOLECULAR BIOLOGY Datum odbrane : 27.12.2012 Mijeloproliferativne neoplazije, JAK2-V617F mutacija, 46/1 haplotip, transkripcionaregulacija, ekspresija JAK2 gena, apoptoza Myeloproliferative neoplasms, JAK2-V617F-mutation, 46/1 haplotype, transcriptionalregulation, expression of the JAK2 gene, apoptosis 616-006.4: 576.352.5]: 577.218 (043.3) Mijeloproliferativne neoplazme Apoptoza 1738 11A02 2012