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Identification of molecular genetic markers of acute myeloid leukemia pathogenesis

dc.contributor.advisorTošić, Nataša
dc.contributor.otherPavlović, Sonja
dc.contributor.otherSavić Pavićević, Dušanka
dc.contributor.otherTošić, Nataša
dc.contributor.otherPavlović, Sonja
dc.creatorMarjanović, Irena M.
dc.date.accessioned2018-04-23T11:29:57Z
dc.date.available2018-04-23T11:29:57Z
dc.date.available2020-07-03T08:04:56Z
dc.date.issued2018-03-12
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=5740
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/9411
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:17563/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025184690
dc.description.abstractAkutna mijeloidna leukemija (AML) predstavlja grupu hematoloških malignih oboljenja koju karakteriše heterogeni genetički i epigenetički profil. AML sa normalnim kariotipom (AML-NK) predstavlja najveću podgrupu u okviru AML, koju odlikuje intermedijarni rizik. Međutim, samo 40% obolelih od AML-NK preživljava duže od 5 godina, pa je neophodno otkriti molekularno-genetičke markere značajne za prognozu i praćenje toka bolesti, rano otkrivanje minimalne rezidualne bolesti (MRB) i izbor odgovarajuće terapije, kako bi bila omogućena bolja stratifikacija pacijenata sa AML-NK. Prvi cilj ove studije je analiza mutacionog profila dečje (dAML) i adultne (aAML) koja će doprineti rasvetljenju patogeneze mijeloidnih leukemija. Drugi cilj predstavlja određivanje nivoa ekspresije WT1, EVI1, BAALC i MN1 gena, kao potencijalnih molekularno-genetičkih markera značajnih za AML-NK. Analizirani su neselektovani DNK uzorci 20 dAML i 20 aAML pacijenata, primenom metode targetovanog sekvenciranja nove generacije (eng. „targeted next generation sequencing“ – NGS), TruSeq Amplicon - Cancer Panel (TSACP) esejem, koji omogućava detekciju somatskih mutacija u 48 gena uključenih u kancerogenezu. U drugom delu ove studije nivo ekspresije gena WT1 (104 pacijenta), EVI1 (104 pacijenta), BAALC (111 pacijenata) i MN1 (111 pacijenata) u mononuklearnim ćelijama koštane srži AML-NK pacijenata i zdravih pojedinaca analiziran je real-time PCR metodom. Rezultati su pokazali da AML sadrži relativno mali broj genetičkih promena, u proseku samo 3 mutacije po pacijentu kod aAML i dAML grupe pacijenata. Zastupljenost najčešćih mutacija u pojedinačnim genima, koji su povezani sa patogenezom AML, razlikovala se kod dAML i aAML: IDH1 (0% kod dAML, 5% kod aAML), IDH2 (0% kod dAML, 10% kod aAML), NPM1 (10% kod dAML, 35% kod aAML). Takođe, prisustvo mutacija u 4 gena (JAK3, ABL1, GNAQ i EGFR) koji kodiraju tirozin kinaze ili proteine koji su udruženi sa tirozin kinazama detektovano je isključivo kod dAML pacijenata, dok je kod 5 gena (IDH1, APC, HNF1A, GNAS i SMARCB1) koji su uključeni u metilaciju i modifikaciju histona prisustvo mutacija utvrđeno isključivo kod aAML pacijenata...sr
dc.description.abstractAcute myeloid leukemia (AML) is a group of haematological malignancies characterized by a heterogeneous genetic and epigenetic profile. AML with normal karyotype (AML-NK) represents the largest subgroup within the AML, characterized by an intermediate risk. However, only 40% of patients with AML-NK survive for more than 5 years, so it is necessary to detect molecular genetic markers significant for prognosis and disease monitoring, early detection of minimum residual disease (MRD), and the selection of appropriate therapy in order to enable better stratification of patients with AML-NK. The first aim of this study is the analysis of the mutation profile of childhood (cAML) and adult (aAML) AML which will contribute to the clarification of the pathogenesis of myeloid leukemia. The second aim is to determine the level of expression of WT1, EVI1, BAALC and MN1 gene, as potential molecular genetic markers relevant to AML-NK. Unselected DNA samples of 20 cAMLs and 20 aAML patients were analyzed using the targeted next generation sequencing (NGS) method, on the TruSeq Amplicon-Cancer Panel (TSACP), which enables the detection of somatic mutations in 48 genes involved in carcinogenesis. In the second part of this research, the level of expression of the genes WT1 (104 patients), EVI1 (104 patients), BAALC (111 patients) and MN1 (111 patients) was analyzed in mononuclear bone marrow cells of AML-NK patients and healthy individuals by the real-time PCR method. The results showed that the AML contains a relatively small number of genetic changes, on average only 3 mutations per patient in the aAML and cAML group. The incidence of the most common mutations in individual genes, which are associated with AML pathogenesis, differed in cAML and aAML: IDH1 (0% in cAML, 5% in aAML), IDH2 (0% in cAML, 10% in aAML), NPM1 (10% in cAML, 35% in aAML). Also, the presence of mutations in 4 genes (JAK3, ABL1, GNAQ, and EGFR) that encode tyrosine kinases or proteins that are associated with tyrosine kinases were detected exclusively in cAML patients, while in 5 genes (IDH1, APC, HNF1A, GNAS and SMARCB1) involved in methylation and histone modification, the presence of mutations was found exclusively in aAML patients...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Integrated and Interdisciplinary Research (IIR or III)/41004/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectakutna mijeloidna leukemija sa normalnim kariotipom (AML-NK)sr
dc.subjectacute myleoid leukemia with normal karyotype (AML-NK)en
dc.subjectNext Generation Sequencing (NGS)sr
dc.subjectWT1 ekspresijasr
dc.subjectEVI1 ekspresijasr
dc.subjectBAALC ekspresijasr
dc.subjectMN1 ekspresijasr
dc.subjectNext Generation Sequencing (NGS)en
dc.subjectWT1 expressionen
dc.subjectEVI1 expressionen
dc.subjectBAALC expressionen
dc.subjectMN1 expressionen
dc.titleIdentifikacija molekularno-genetičkih markera patogeneze akutne mijeloidne leukemijesr
dc.title.alternativeIdentification of molecular genetic markers of acute myeloid leukemia pathogenesisen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dcterms.abstractТошић, Наташа; Павловић, Соња; Тошић, Наташа; Савић Павићевић, Душанка; Павловић, Соња; Марјановић, Ирена М.; Идентификација молекуларно-генетичких маркера патогенезе акутне мијелоидне леукемије; Идентификација молекуларно-генетичких маркера патогенезе акутне мијелоидне леукемије;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/936/IzvestajKomisije16057.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/935/Disertacija.pdf


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