ATRA - differentiation leukemia therapy

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.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