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Preučevanje mehanizmov odpornosti celic kronične limfocitne levkemije na sodobno terapijo = Investigating the resistance mechanisms of chronic lymphocytic leukemia cells towards contemporary therapies : enoviti magistrski študijski program FarmacijaDragović, AnđelaKronična limfocitna levkemija (KLL) predstavlja najpogostejšo obliko levkemije pri odraslih, za katero je značilno kopičenje limfocitov B v krvi, kostnem mozgu in limfatičnih organih. V sodobnem času ... temelji zdravljenje KLL na uporabi tarčnih zdravil. Mednje spadajo zaviralci Brutonove tirozin kinaze (BTK), kot sta ibrutinib in akalabrutinib, ter zaviralci fosfatidilinozitol 3-kinaze (PI3K), idelalizib in duvelizib. S tega vidika smo v okviru magistrske naloge preučili mehanizme odpornosti na zaviralce PI3K in BTK ter tako ponudili nove možnosti za njeno premagovanje pri KLL. Zaradi nezadostno razvitih modelov za preučevanje mehanizmov odpornosti smo uporabili novo razvite celične linije MEC-1, ki so odporne na ibrutinib, akalabrutinib, idelalizib in duvelizib. Na teh celicah smo preverili izražanje proteinov preživetvenih poti B-celičnega receptorja (BCR). Najprej smo z metodo prenosa western preverili izražanje antiapoptotičnih proteinov Mcl-1, Bcl-2 in Bcl-xL in ugotovili, da je protein Bcl-xL povišano izražen v odpornih celicah. Nato pa smo s testom PrestoBlue ugotovili, da s selektivnim zaviranjem Bcl-xL skupaj z zaviranjem PI3K sinergistično zmanjšamo metabolno aktivnost celic, odpornih na idelalizib in duvelizib, ter posledično premagamo odpornost. Nato smo vzroke za odpornost celic na zaviralce BTK in PI3K iskali v spremenjenem izražanju signalnih poti BCR. S prenosom western nismo zaznali sprememb v izražanju proteinov signalne poti BTK/PLCγ2. Z uporabo pretočne citometrije smo ugotovili konstitutivno povišano izražanje PI3K in c-Myc v odpornih celicah, s čimer smo izpostavili pomen povezave signalne poti PI3K in onkogenega proteina c-Myc pri odpornosti na idelalizib in duvelizib. Na koncu smo se osredotočili na vlogo signalne poti NF-κB pri odpornosti na zaviralce PI3K. V odpornih celicah smo zaznali povečano izražanje NF-κB. Povezavo med signalno potjo PI3K in NF-κB smo potrdili z uporabo aktivatorjev NF-κB (PMA/ionomicin, sCD40L) na celicah bolnikov s KLL, ki so zmanjšali citotoksičnost zaviralcev PI3K. Ker zaviralci proteasoma (cP) in imunoproteasoma (iP) zavirajo NF-κB, smo preverili ali lahko z njimi premostimo odpornost na zaviralce PI3K. Z uporabo selektivnega zaviralca cP karfilzomiba in zaviralca iP ONX-0914 v kombinaciji z zaviralci PI3K smo dosegli sinergistično citotoksičnost na celice MEC-1, odporne na idelalizib in duvelizib. Na podlagi tega rezultata smo sočasno uporabo zaviralcev PI3K in cP/iP predlagali kot novo možnost za premagovanje odpornosti pri KLL.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [A. Dragović], 2023Language - slovenianCOBISS.SI-ID - 164791299
Author
Dragović, Anđela
Other authors
Mlinarič-Raščan, Irena |
Avsec, Damjan, farmacevt, 1993-
Topics
Kronična limfocitna levkemija |
fosfatidilinozitol 3-kinaza |
PI3K |
NF-κB |
idelalizib |
duvelizib |
proteasom |
imunoproteasom |
karfilzomib |
ONX-0914 |
odpornost
Library/institution |
City | Acronym | For loan | Other holdings |
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Dragović, Anđela | |
Mlinarič-Raščan, Irena | 12443 |
Avsec, Damjan, farmacevt, 1993- | 52092 |
Source: Personal bibliographies
and: SICRIS
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