ATRA - diferencijacijska terapija leukemije

undergraduate thesis

• Title (english): ATRA - differentiation leukemia therapy
• Author: Biljana Sasi
• Mentor: Inga Marijanović (mentor)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2012, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Glavninu ovog rada čini opis mijelopoeze, diferencijacijskog puta od mijeloidnog prekursora do konačne linije granulocita (neutrofili, eozinofili, bazofili) i agranulocita (monociti/makrofagi). Narušavanje mehanizama diferencijacije inhibicijom diferencijacijskih faktora i biosignalnih puteva Ras/Raf/MEK/ERK i PI3K/Akt/mTOR/S6K dovodi do prekomjernog stvaranja nedovoljno zrelih stanica, pri čemu se one akumuliraju u koštanoj srži i u krvotoku, pa se kao posljedica javlja leukemija. Inače, APL opisujemo kao bolest s fatalnim ishodom u roku od samo nekoliko tjedana nakon dijagnoze, a okarakterizirana je uravnoteženom recipročnom translokacijom između kromosoma 15 i 17 što rezultira fuzijom PML gena i receptora retinoične kiseline α (RARα). Takva fuzija uzrokuje konformacijsku promjenu pri čemu ko-represor HDAC ostaje vezan za fuzijski protein PML/RARα i pri fiziološkim koncentracijama RA. Posljedica toga je povećana proliferacija abnormalnih promijelocita, te je time narušena normalna diferencijacija do granulocita. Međutim, klinička primjena ATRA i ATO u liječenju APL postiže značajan uspjeh, zbog svojih važnih svojstava modifikacije i razgradnje fuzijskog proteina PML/RARα posredovanih unutarstaničnim kaspazama i citoplazmatskim kompleksom proteasomom.

Abstract (english)

The bulk of this work is the description of myelopoiesis, differentiation pathway from the myeloid precursor to the final lineage of granulocytes (neutrophils, eosinophils, basophils) and agranulocytes (monocytes/macrophages). Disruption of differentiation mechanisms, as inhibition of lineage-specific differentiation factors and biosignalisation pathways Ras/Raf/MEK/ERK and PI3K/Akt/mTOR/S6K leads to excessive formation of immature cells, where they accumulate in the bone marrow and the bloodstream, so it all results with leukemia. Otherwise, APL is described as a disease with a fatal outcome within only a few weeks after diagnosis and is characterized by a balanced reciprocal translocation between chromosomes 15 and 17. The result is a fusion between PML gene and retinoic acid receptor α (RARα) which causes a conformational change whereby co-repressor HDAC remains bound to this newly synthesized hybrid protein PML/RARα at physiological concentrations of RA. The final consequence is an increased proliferation of abnormal promyelocytes. All that leads to disruption of normal differentiation toward granulocytes. However, a clinical application of ATRA and ATO in APL treatment achieved a considerable success. Importanly, ATRA and ATO properties such as enhanced modification or degradation of PML/RARα oncoprotein, mediated by intracellular caspases and a cytoplasmic complex proteasome, might provide a plausible explanation for the appreciable efficacy of this combination therapy in APL patients.

• Keywords: akutna promijelocitna leukemija; sve-trans-retinoična kiselina
• Keywords (english): acute promyelocytic leukemia; all-trans-retinoic acid
• Language: croatian
• URN:NBN: urn:nbn:hr:217:247155
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: undergraduate; Academic / professional title: sveučilišni/a prvostupnik/prvostupnica (baccalaureus/baccalaurea) molekularne biologije (sveučilišni/a prvostupnik/prvostupnica (baccalaureus/baccalaurea) molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2018-04-20 10:22:31