Naslov (srp)

Prognostički i prediktivni značaj polimorfizama i ekspresije gena za proteine uključene u transport i metabolizam citarabina i antraciklina i regulaciju apoptoze u akutnoj mijeloidnoj leukemiji odraslih : doktorska disertacija

Autor

Pravdić, Zlatko, 1991-

Doprinosi

Pavlović, Sonja, 1960-
Plješ -Ercegovac, Marija, 1976-
Vidović, Ana, 1962-
Savić, Aleksandar, 1963-
Suvajdžić Vuković, Nada, 1960-
Mitrović, Mirjana, 1978-

Opis (eng)

Background: Remarkable differences in therapy response among acute myeloid leukaemia(AML) patients, treated with standard cytarabine-anthracycline remission induction chemotherapy,could be partly explained by the patients’ genetic variability related to metabolic paths of cytarabineand anthracyclines and dysregulation of apoptosis. The aim of this study is to evaluate the effect ofpolymorphisms in pharmacogenes SLC29A1 (solute carrier family 29 member 1), DCK(deoxycytidine kinase), ABCB1 (ATP binding cassette subfamily B member 1), GSTM1 and GSTT1(glutathione-S transferases M1 and T1) and gene expression profiles of anti-apoptotic BCL2 (B-cellleukaemia 2), pro-apoptotic BAX (BCL2 associated X) and multi-drug resistance (ABCB1), as well aslaboratory and AML-related parameters on clinical outcomes and survival in adult AML patients.Methods: A total of 100 AML patients were included in the study. Pharmacogeneticpolymorphisms SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582, GSTM1 and GSTT1gene deletions were detected by methodology based on PCR, fragment analysis and directsequencing. In subgroup of 51 normal karyotype (NK) AML patients the expression of BCL2, BAXand ABCB1 was analysed by PCR. All of the analyses were performed form bone marrow specimensobtained at diagnosis. Descriptive, analytic and survival (using Kaplan-Meier method / Log-Ranktest) statistical analysis were performed.Results: This is the first study of pharmacogenetics and pharmacotranscriptomics in adultSerbian AML population. Clinical outcomes in our cohort of AML patients were not impacted byanalysed polymorphisms in SLC29A1, DCK, ABCB1, GSTM1 and GSTT1 genes, independently or incombinations. Achievement of complete remission (CR) was identified as an independent prognosticindicator of clinical outcome. Subgroup analysis of NK AML patients showed high expression ofBCL2 (BCL2+) was associated with chemoresistance (p=0.024), while patients with decreased BAXexpression were susceptible to relapse (p=0.047). Joint effects of the BCL2 and BAX expressionrevealed that 87% of patients with BAX/BCL2low were chemo resistant (p=0.044). Increased ABCB1expression corelated with BCL2+ (p<0.001) and with absence FLT3-ITD (fms related receptortyrosine kinase 3 inter tandem duplication) mutations (p=0.019).Conclusions: polymorphisms of SLC29A1, DCK, ABCB1, GSTT1 and GSTM1 didn’tinfluence clinical outcomes, either independently or in combinations. Subgroup analysis of NK AMLpatients revealed that high BCL2 expression was related with chemoresistance while low expressionof BAX with grater relapse rate. In addition, the patients with BAX/BLC2low status experienced primaryrefractoriness more frequently. Moreover, achievement of CR, in multivariate analysis, wasindependent and unique predictor of disease free and overall survival in our cohort of adult newlydiagnosed AML patients.

Opis (srp)

Uvod: Značajne razlike u odgovoru na standardnu indukcionu terapiju, zasnovanu nacitarabinu i antraciklinu, u odraslih bolesnika sa akutnom mijeloidnom leukemijom (AML),delimično bi se mogle objasniti genetičkim varijabilitetom metaboličkih puteva citarabina iantraciklina, kao i poremećenoj regulaciji apoptoze. Cilj ovog istraživanja bilo je ispitivanje uticajapolimorfizama u farmakogenima SLC29A1 (engl. solute carrier family 29 member 1), DCK (gen zadeoksicitidin kinazu), ABCB1 (engl. ATP binding cassette subfamily B member 1), GSTM1 i GSTT1(geni za glutation-S transferaze M1 i T1) i ekpsresije antiapoptotskog BCL2 (engl. B-cell leukaemia2) i proapoptotskog BAX (engl. BCL2 associated X) i gena rezistencije na lekove (ABCB1), sa jednestrane i demografksih, kliničkih, laboratorijskih i parametara vezanih za AML, sa druge strane, naishode lečenja odraslih bolesnika sa AML.Materijal i metode. Ukupno 100 bolesnika sa AML uključeno je u studiju. Farmakogenetičkipolimorfizmi SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582 i delecije gena GSTM1 iGSTT1 određivane su metodologijom zasnovanom na PCR-u, analizom fragmenata i direktnimsekvenciranjem. U podgrupi pedesetjednog bolesnika sa AML i normalnim kariotipom (NK),analizirane su ekspresije gena BCL2, BAX i ABCB1 PCR-om. Sve analize su sprovedene na uzorcimakoštane srži uzete na dijagnozi. Korišćene su metode deskriptivne i analitičke statistike. Analizapreživljavanja je sprovedena prema Kaplan-Majerovom metodu upotrebom Log-Rank testa.Rezultati. Ovo je prva farmakogenetička i farmakotranskriptomička studija odraslih bolesnikasa AML u srpskoj populaciji. Polimorfizmi u genima SLC29A1, DCK, ABCB1, GSTM1 i GSTT1 nisuuticale na ishode lečenja u našoj kohorti obolelih od AML, samostalno ili u međusobnimkombinacijama. Međutim, postizanje kompletne remisije (KR) bolesti istaklo se kao nezavisniprediktor ishoda lečenja. Analiza u podgrupi NK AML bolesnika pokazala je da je povećanaekspresija BCL2 (BCL2+) udružena sa pojavom rezistencije (p=0,024), snižena ekspresija BAX-a sarelapsom (p=0,047), dok je u analizi združenog uticaja BAX-a i BLC2, 87% bolesnika saBAX/BCL2nizak statusom bilo primarno refraktarno (p=0.044). Povišena ekspresija ABCB1 bila jeudružena sa BCL2+ statusom (p<0.001) i odsustvom mutacije FLT3-ITD (engl. fms related receptortyrosine kinase 3 inter tandem duplication) (p=0.019).Zaključci. Polimorfizmi gena SLC29A1, DCK, ABCB1, GSTM1 i GSTT1 nisu uticali na ishodelečenja i preživljavanje, pojedinačno ili u međusobnim kombinacijama. U podgrupi NK AMLbolesnika uočeni su: veća stopa rezistencije kod visoke ekspresije BCL2, veća stopa relapsa kod niskeekspresije BAX-a i češća primarna refraktarnost u onih sa BAX/BLC2nizak statusom. Postizanje KR, umultivarijantnoj analizi, istaklo se kao nezavisni i jedini prediktor preživljavanja bez bolesti iukupnog preživljavanja u našoj grupi odraslih novodijagnostikovanih bolesnika sa AML.

Opis (srp)

Interna medicina - Biologija tumora i oksidativna oboljenja / Internal medicineInternal medicine - Tumor biology and oxidative diseases Datum odbrane: 30.09.2024.

Jezik

srpski

Datum

2024

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-NC-ND 3.0 AT - Creative Commons Autorstvo - Nekomercijalno - Bez prerada 3.0 Austria License.

http://creativecommons.org/licenses/by-nc-nd/3.0/at/legalcode

Predmet

OSNO - Opšta sistematizacija naučnih oblasti, Hematopoezni sistem. Limfni sistem

acute myeloid leukaemia, cytarabine, anthracyclines, gene polymorphisms, SLC29A1, DCK, ABCB1, GST, BCL2, BAX

OSNO - Opšta sistematizacija naučnih oblasti, Hematopoezni sistem. Limfni sistem

akutna mijeloidna leukemija, citarabin, antraciklini, polimorfizmi gena, SLC29A1, DCK, ABCB1, GST, BCL2, BAX

616.155.392:577.2(043.3)