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doctoral thesis
Mehanizam diferencijacije stanica akutne mijeloične leukemije potaknute citarabinom
Zagreb: University of Zagreb, School of Medicine, 2024. urn:nbn:hr:105:023718
Smoljo, Tomislav
University of Zagreb
School of Medicine

Institutional repository: Dr Med - University of Zagreb School of Medicine Digital Repository

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Smoljo, T. (2024). Mehanizam diferencijacije stanica akutne mijeloične leukemije potaknute citarabinom (Doctoral thesis). Zagreb: University of Zagreb, School of Medicine. Retrieved from https://urn.nsk.hr/urn:nbn:hr:105:023718

Smoljo, Tomislav. "Mehanizam diferencijacije stanica akutne mijeloične leukemije potaknute citarabinom." Doctoral thesis, University of Zagreb, School of Medicine, 2024. https://urn.nsk.hr/urn:nbn:hr:105:023718

Smoljo, Tomislav. "Mehanizam diferencijacije stanica akutne mijeloične leukemije potaknute citarabinom." Doctoral thesis, University of Zagreb, School of Medicine, 2024. https://urn.nsk.hr/urn:nbn:hr:105:023718

Smoljo, T. (2024). 'Mehanizam diferencijacije stanica akutne mijeloične leukemije potaknute citarabinom', Doctoral thesis, University of Zagreb, School of Medicine, accessed 10 June 2024, https://urn.nsk.hr/urn:nbn:hr:105:023718

Smoljo T. Mehanizam diferencijacije stanica akutne mijeloične leukemije potaknute citarabinom [Doctoral thesis]. Zagreb: University of Zagreb, School of Medicine; 2024 [cited 2024 June 10] Available at: https://urn.nsk.hr/urn:nbn:hr:105:023718

T. Smoljo, "Mehanizam diferencijacije stanica akutne mijeloične leukemije potaknute citarabinom", Doctoral thesis, University of Zagreb, School of Medicine, Zagreb, 2024. Available at: https://urn.nsk.hr/urn:nbn:hr:105:023718

Metadata
TitleMehanizam diferencijacije stanica akutne mijeloične leukemije potaknute citarabinom
Title (english)The mechanism of cytarabine-induced differentiation of acute myeloid leukemia cells
AuthorTomislav Smoljo
MentorDora Višnjić (mentor)
Committee memberRajko Kušec (predsjednik povjerenstva)
Committee memberDanka Grčević (član povjerenstva)
Committee memberRadovan Vrhovac (član povjerenstva)
GranterUniversity of Zagreb
School of Medicine
Zagreb
Defense date and country2024-04-26, Croatia
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Basic Medical Sciences
Cytology, Histology and Embryology
Universal decimal classification
(UDC)		61 - Medical sciences
Abstract
Citarabin u malim koncentracijama potiče diferencijaciju stanica akutne mijeloične leukemije (AML), ali mehanizam nije u potpunosti objašnjen. Naša prethodna istraživanja pokazala su da inhibitori sinteze pirimidina potiču diferencijaciju leukemijskih stanica aktivacijom kinaze Chk1 (prema engl. checkpoint kinase 1). Cilj ovog istraživanja je ispitati ulogu Chk1 u diferencijaciji leukemijskih stanica potaknutoj citarabinom te ispitati učinke stromalnih stanica na diferencijaciju leukemijskih stanica. Leukemijske stanične linije U937, THP-1 i MOLM-13, te stromalnu staničnu liniju MS-5 smo tretirali citarabinom i inhibitorima sinteze pirimidina. Koristeći Western blot, protočnu citometriju, farmakološke inhibitore i siRNA transfekciju pokazali smo da niska doza citarabina uzrokuje diferencijaciju aktivacijom Chk1. Prisutnost stromalnih stanica smanjuje učinke niskih doza citarabina na zastoj u staničnom ciklusu, signalizaciju oštećenja DNA i diferencijaciju stanica AML-a. Iako je sekvenciranje RNA pokazalo da stroma smanjuje izražaj gena uključenih u signalizaciju citokinima i oksidativni stres, rezultati dobiveni pomoću farmakoloških inhibitora i neutralizirajućih protutijela nisu podržali ulogu CXCL12, TGF- i slobodnih radikala kisika. Ovi rezultati pokazuju da niska doza citarabina potiče diferencijaciju leukemijskih stanica aktivacijom kinaze Chk1 te da stromalne stanice smanjuju diferencijaciju stanica AML-a potaknutu niskim dozama citarabina in vitro.
Abstract (english)
Low-dose cytarabine promotes differentiation of acute myeloid leukemia (AML) cells, but the mechanism is not fully elucidated. Our previous research showed that pyrimidine synthesis inhibitors stimulate the differentiation of AML cells by activating checkpoint kinase 1 (Chk1). This research aims to investigate the role of Chk1 in the cytarabine-induced differentiation of AML cells and to examine the effects of stromal cells on AML differentiation. Leukemia cell lines U937, THP-1, and MOLM-13, and stromal cell line MS-5 were treated with cytarabine and pyrimidine synthesis inhibitors. Using immunoblotting, flow cytometry analyses, pharmacologic inhibitors, and genetic inactivation of Chk1 we show that low-dose cytarabine induces differentiation by activating Chk1. The presence of stromal cells prevented cell cycle arrest, DNA damage signaling, and AML cells differentiation induced by low-dose cytarabine. Although transcriptomic analysis revealed that the stroma reduced the expression of genes involved in cytokine signaling, and oxidative stress, data obtained with pharmacological inhibitors and neutralizing antibodies did not support the role of CXCL12, TGF-β, or reactive oxygen species. This study reveals that that low-dose cytarabine promotes leukemic cell differentiation by activating Chk1 kinase and that stromal cells reduce low-dose cytarabine-induced AML differentiation in vitro.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:105:023718
Promotion2024
ProjectNumber: IP-2016-06-4581
Title: Signalni mehanizmi i metaboličke promjene u diferencijaciji stanica akutne mijeloične leukemije
Title: Signaling mechanisms and metabolic changes in differentiation of acute leukemia cells
Acronym: SignalmetabAML
Leader: Dora Višnjić
Jurisdiction: Croatia
Funder: Hrvatska zaklada za znanost
Funding stream: Research Projects
ProjectNumber: IP 2022-10-9146
Title: Oštećenje DNA i diferencijacija akutne mijeloične leukemije”
Leader: Dora Višnjić
Jurisdiction: Croatia
Funder: Hrvatska zaklada za znanost
Funding stream: Research Projects
ProjectNumber: KK.01.1.1.01.0007
Title: Znanstveni centar izvrsnosti - eksperimentalna i klinička istraživanja hipoksijsko-ishemijskog oštećenja mozga u perinatalnoj i odrasloj dobi
Title: Scientific center of excellence - Experimental and clinical research of hypoxic-ischemic brain damage in perinatal and adulthood
Acronym: ZCI-NEURO
Leader: Miloš Judaš
Jurisdiction: eu
Funder: Europska komisija
Funding stream: European Regional Development Fund
Study programmeTitle: Biomedicine and Health Sciences
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
Type of resourceText
Extent91 str.
File originBorn digital
Access conditionsOpen access
Terms of useLicence In copyright icon
Created on2024-05-10 11:24:38