C-kit mutacija u akutnoj mijeloičnoj leukemiji s preuredbom gena grupe CBF

master's thesis

• Title (english): C-kit mutation in acute myeloid leukemia with CBF- gene rearrangement
• Author: Jakov Bilać
• Mentor: Rajko Kušec (mentor)
• Committee member: Vlatko Pejša (predsjednik povjerenstva)
• Committee member: Jasenka Markeljević (član povjerenstva)
• Committee member: Rajko Kušec (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Internal Medicine); Zagreb
• Defense date and country: 2019-07-12, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Internal Medicine

Abstract

Akutna mijeloična leukemija s preuredbom gena grupe CBF se citogenetski definira prisutnošću t(8;21)(q22;q22) ili inv(16)(p13;q22)/t(16;16)(p13;q22) i ona čini 15% svih slučajeva de novo AML-a u odraslih. Na molekularnoj razini, obje kromosomske promjene dovode do poremećaja funkcije CBF-a, heterodimernog transkripcijskog faktora koji regulira normalnu hematopoezu. Mutacije CBF gena rezultiraju zaustavljanjem diferencijacije i povećanjem sposobnosti samoobnavljanja hematopoetskih progenitora te na taj način sudjeluju u leukemijskoj transformaciji. Unatoč mnogim zajedničkim karakteristikama, istraživanja pokazuju značajne genetske, kliničke i prognostičke razlike izmeĎu AML-a s t(8;21) odnosno inv(16) što upućuje na činjenicu da ih treba razmatrati kao dva zasebna entiteta. Iako se bolesnici s CBF AML-om svrstavaju u skupinu s povoljnom prognozom, trenutnim načinom liječenja samo polovica uspijeva ostvariti dugogodišnje preživljenje. U svrhu poboljšanja ishoda liječenja potrebna je bolja stratifikacija rizika na temelju kliničkih i/ili genetskih čimbenika te razvoj ciljane antitumorske terapije. Dobar kandidat za to su mutacije KIT gena koje se mogu pronaći u rasponu od 17% do čak 46% slučajeva CBF AML-a, što ih čini najučestalijim mutacijama u ovoj skupini. One dovode do konstitucijske aktivnosti c-kit receptora koji tada neovisno o prisutnosti liganda potiče stanicu na proliferaciju. U ovom radu bit će prikazana dosadašnja saznanja o prognostičkoj i terapijskoj vrijednosti KIT mutacija u CBF AML-u.

Abstract (english)

Core binding factor (CBF) acute myeloid leukemia (AML) is cytogenetically defined by the presence of t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) and constitues approximately 15% of all adult de novo AML cases. At the molecular level, both chromosome changes result in disruption of CBF, a heterodimeric transcription factor that functions as an essential regulator of normal hematopoiesis. Mutations in CBF-encoding genes result in disruption of differentiation and increased self-renewal capacity of the hematopoietic progenitors thus contribute to leukemogenesis. Despite numerous similarities, studies demonstrate significant differences in genetic, clinical, and prognostic features between t(8;21) and inv(16)/t(16;16) AML, thereby supporting the notion that they represent two distinct entities. Although CBF AML patients are considered to have relatively good prognosis, only approximately half of the CBF AML patients achieve long-term survival with current therapy. Improvements in risk stratification based upon clinical and/or genetic factors and development of targeted therapies are needed for better outcomes. KIT mutations, most common mutations found in 17-46% of CBF AML cases, are considered to be good potential molecular marker. They lead to constitutional activity of c-kit receptor which in turn induces ligand-independent cell proliferation. This review provides overview of current knowledge regarding prognostic and therapeutic value of KIT mutations in CBF AML.

• Keywords: CBF AML; KIT mutacije; stratifikacija rizika; ciljana terapija
• Keywords (english): CBF AML; KIT mutations; risk stratification; targeted therapy
• Language: croatian
• URN:NBN: urn:nbn:hr:105:016299
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2020-01-08 15:50:05