Molekularni mehanizmi patogeneze mijeloproliferativnih neoplazija : poremećaj ekspresije gena uključenih u proliferaciju i apoptozu
Molecular mechanisms of pathogenesis of myeloproliferative neoplasms: deregulation of genes involved in cell proliferation and apoptosis
Author
Spasovski, Vesna M.Mentor
Pavlović, SonjaCommittee members
Pavlović, SonjaSavić-Pavićević, Dušanka
Savić-Pavićević, Dušanka
Nikčević, Gordana
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Show full item recordAbstract
Mijeloproliferativne neoplazije (MPN) su hronični hematološki maligniteti koji se odlikuju
autonomnom proliferacijom opredeljenih progenitora hematopoeze i aberantnom aktivacijom
tirozin kinaznih signalnih puteva u kombinaciji sa snažnim odgovorom na citokine i faktore rasta.
Tri bolesti predstavljaju MPN u užem smislu: policitemija vera (PV), esencijalna trombocitemija
(ET) i mijelofibroza (MF). Jedna od komplikacija ovih oboljenja je njihova kasna evolucija u
akutnu mijeloidnu leukemiju (AML).
Važno obeležje ovih bolesti ja prisustvo „missense“ JAK2-V617F mutacije u sve tri bolesti,
a procenat zastupljenosti mutacije po bolestima je različit. TakoĎe pokazano je da kod ovih
pacijenata postoji tzv. efekat “doze gena”, odnosno da različit nivo V617F alela utiče kliničku sliku
bolesti.
JAK2-V617F mutacija dogaĎa se u 80% slučajeva na specifičnom haplotipu koji je nazvan
46/1 haplotip. Na koji način ovaj niz SNP-ova, koji se nalaze u JAK2 genu, predisponira nastajanje
mutacije kao i njen ...uticaj na fenotip MPN, još nije utvrĎeno. Jedan od mogućih mehanizama je
uticaj ovog haplotipa na transkripciju. Posebnu pažnju u okviru 46/1 haplotipa je privukao SNP
rs12343867, koji u potpunosti asocira sa MPN.
Proces apoptoze je deregulisan u hematološkim malignitetima, što dovodi do rezistencije
malignih ćelija na signale smrti i obezbeĎuje im duži život u odnosu na normalne ćelije. Proces
apoptoze nije detaljno izučen kod MPN, mada se zna da je direktno pogoĎen JAK2-V617F
mutacijom. Naime, glavni signalni put preko STAT5 (Signal Transducers and Activators of
Transcription) proteina direktno aktivira anti- apoptotski BCL2-xL protein, čime se smanjuje
apoptoza. Deregulacija ostalih apoptotskih puteva u MPN nije u potpunosti rasvetljena
Myeloproliferative neoplasms (MPN) are chronic hematological
malignancies that are characterized by autonomous proliferation of committed
hematopoietic progenitors and aberrant activation of tyrosine kinase signaling pathways, in
combination with a strong response to cytokines and growth factors. Three major entities
constitute MPN: polycythaemia vera (PV), essential thrombocythemia (ET) and primary
myelofibrosis (PMF). One of the complications of these diseases is their late evolution into
acute myeloid leukemia.
Important feature of these diseases is the presence of missense mutation JAK2-
V617F and its variable representation among MPN entities. It is also shown that there is socalled
effect of "gene dosage" in these patients, meaning that a different level of V617F
alleles influences the clinical picture of the disorders.
JAK2-V617F mutation occurs in 80% of cases on a specific haplotype, called 46/1
haplotype. Exact mechanism of action of this set of SNPs, that are located within ...the JAK2
gene, has not been determined yet. One of the possible mechanisms could be that it effects
transcription. Among eight SNPs, included in this haplotype, SNP rs12343867 has drawn
special attention because of its strong association with the MPN.
The process of apoptosis is deregulated in hematological malignancies, leading to
resistance of cancer cells to death signals, thus providing them a longer life span compared
to normal cells. The process of apoptosis has not been extensively studied in MPN,
although it is known that it is directly affected by the JAK2-V617F mutation. Specifically, the main signaling pathway through STAT5 protein directly activates anti-apoptotic BCL2-
xL protein, thereby reducing apoptosis. Deregulation of other apoptotic pathways in MPN
is not fully understood