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Bonamigo, Emanuela (2013) Trombocitosi ed eritrocitosi pediatriche: studi biologici e biomolecolari in 149 bambini studiati presso i centri di emato-oncologia pediatrica italiani. [Tesi di dottorato]

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Abstract (inglese)

Chronic Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) include polycythemia vera (PV), essential thrombocythemia (TE) and primary myelofibrosis (PMF). They are clonal diseases of the stem cell, typically affecting patients in middle-advanced age; they are extremely rare in pediatrics: in the literature only some case reports or small cohorts are found.
At the base of these diseases there is an altered signaling, as evidenced by the presence of the JAK2V617F mutation in approximately 70% of adult patients (95% PV, 50-60% in ET and PMF).
In adults, other rare mutations were identified in addition to JAK2V617F. In particular respectively 1% and 5% of cases of ET and PMF are characterized by the presence of W515L, W515K, W515A mutations of thrombopoietin receptor (MPL). Other mutations on MPL and thrombopoietin (TPO) have been found in familiar Ph-MPN.
In adults PV patients other JAK2 gene mutations were identified on exon 12 (3%).
Rare familial forms with increased serum erythropoietin (EPO) levels are due to mutations of the oxygen sensing pathway (HIF2α, PHD2, VHL genes); others with decreased EPO are associated to EPO receptor (EPOR) gene.
Paediatric MPN, when compared to adult MPN, seem to have different biological characteristics, but few data are published on this subject.
In the absence of established criteria for diagnosis, prognosis and therapeutic approach in children with MPN, a European registry of paediatric ET is built, in collaboration with the Italian Institution for Paediatric Haematology (AIEOP).
The collection of clinical and biological data on children with MPN might help in drawing correlations, in identifying differences between children and adults, in order to establish diagnostic and prognostic criteria and therapeutic guidelines, specific for the pediatric age.
ERG gene is involved in the pathogenesis of many cancers including prostate cancer, breast cancer, thyroid cancer and acute leukemia in adults. ERG is also expressed in haemopoiesis, angiogenesis, regulation of inflammation and osteogenesis. Recently ERG highlighted a role in the regulation of hematopoietic stem cells and embryonic and adult megakaryocytic maturation. In particular the overexpression of ERG induces an increase in STAT3 phosphorylation and increased intracellular levels of JAK2 and STAT5.
In hematology ERG gene expression was analyzed only in cases of pediatric and adult acute leukemia.
The purpose of the study is to evaluate the importance of gene ERG in the pathogenesis of pediatric chronic myeloproliferative neoplasms. In children chronic myeloproliferative neoplasms are not characterized by a specific marker of clonality. Therefore it is difficult to distinguish with absolute certainty from secondary forms of thrombocytosis and polyglobulia, which are extremely common in children.
Telomeres are the ends of linear chromosomes and are constituted of repeated DNA sequences associated with specific proteins.
Different studies had shown that, in patients with haematological tumour, leukocytes telomere length is shortened.
Some recent studies have reported a marked telomere length reduction in patient with Ph-negative Chronic Myeloproliferative Neoplasms. This support the possible influence of telomere length in the development of this diseases. Moreover , telomere length might be a putative indicator of the rate of neoplastic proliferation.
The aim of this study is evaluating telomere length in paediatric patients with thrombocytosis and erythrocytosis.

Abstract (italiano)

Le Neoplasie Mieloproliferative croniche (MPN) Filadelfia negative (Ph-MPN) comprendono la Policitemia Vera (PV), la Trombocitemia Essenziale (TE) e la Mielofibrosi Primaria (PMF). Sono patologie clonali derivate dalla trasformazione di una cellula progenitrice emopoietica pluripotente. Sono tipiche dell’età medio-avanzata, mentre sono molto rare in età pediatrica: i casi descritti in letteratura sono spesso case reports o casistiche di piccoli numeri.
Alla base di queste patologie c’è un signaling alterato, come dimostrato dalla presenza della mutazione JAK2V617F in circa il 70% dei pazienti adulti (95% nei PV, 50-60% nelle ET e nelle PMF).
Negli adulti, oltre alla mutazione JAK2V617F sono state identificate altre rare mutazioni. In particolare rispettivamente l’1% e il 5% dei casi di ET e di PMF sono caratterizzati dalla presenza delle mutazioni W515L, W515K e W515A del recettore della trombopoietina (MPL). Altre mutazioni di MPL e della trombopoietina (TPO) sono state osservate in casi familiari di MPN.
Per quanto riguarda i casi di pazienti con PV, negli adulti sono state identificate altre mutazioni a carico dell’esone 12 del gene JAK2 (3%).
Rare forme familiari di eritrocitosi con aumento della eritroietina sierica (EPO-S) sono associate a mutazioni dell’oxigen sensing pathway (geni di HIF2α, PHD2, VHL); altre con EPO-S ridotta sono dovute a mutazioni del recettore dell’EPO (EPO-R).
La letteratura suggerisce che le Ph-MPN nel bambino abbiano caratteristiche diverse da quelle nell’adulto, anche se i dati in tal senso sono esigui. Si differenziano infatti per biologia, frequenza, clinica e prognosi. Inoltre non esiste alcuna documentazione oggettiva che possa guidare nelle scelte terapeutiche più opportune, efficaci e prive di rischi. Nel tentativo di chiarire la natura e la patogenesi di questi disordini pediatrici, è stato costruito un registro europeo della ET pediatriche, la forma meno rara in questa fascia d’età, da noi coordinato. In questo progetto sono coinvolte le Unità di Ricerca appartenenti alla Associazione italiana di Emato-Oncologia Pediatrica (AIEOP) ed indirettamente anche altre strutture afferenti a tale associazione.
La raccolta dei dati clinici e biologici dei bambini con Ph-MPN può permettere di correlarli tra loro, di comprendere eventuali differenze tra forme adulte e pediatriche, di identificare criteri prognostici al fine di proporre linee diagnostiche e terapeutiche specifiche per l’età pediatrica.
Il gene ERG è coinvolto nella patogenesi di molte neoplasie tra cui il carcinoma prostatico, il carcinoma mammario, il carcinoma tiroideo e le leucemie acute degli adulti. Fisiologicamente è stato dimostrato il ruolo di ERG nell’ematopoiesi, nell’angiogenesi, nella regolazione dell’infiammazion e nell’osteogenesi. Recentemente è stata messa in evidenza l’importanza del gene ERG nella regolazione delle cellule staminali emopoietiche sia embrionali che dell’adulto e nella maturazione megacariocitaria. In particolare l’overespressione di ERG sembra indurre un aumento della fosforilazione di STAT3 ed un aumento dei livelli intracellulari di JAK2 e STAT5a.
Fino ad oggi in ematologia l’espressione del gene ERG è stata analizzata solo in casi di leucemia acuta pediatrica e dell’adulto.
Lo scopo dello studio è valutare l’importanza dell’espressione del gene ERG nella patogenesi delle neoplasie mieloproliferative croniche pediatriche che, a differenza di quanto accade nell’adulto, non sono caratterizzate da un marcatore di clonalità specifico che permetta di distinguerle con assolta certezza da forme secondarie di trombocitosi e eritrocitosi, peraltro estremamente frequenti nel bambino.
I telomeri sono sequenze nucleotidiche ripetute associate a specifiche proteine che costituiscono le estremità fisiche dei cromosomi.
Studi differenti dimostrano che, in pazienti con tumori ematologici, la lunghezza del telomero di leucociti è ridotta.
Studi recenti hanno riportato una marcata riduzione della lunghezza del telomero in pazienti con Neoplasie Mieloproliferative croniche Ph-negative. Questo suggerisce una possibile influenza della lunghezza del telomero nello sviluppo di queste patologie. Inoltre, la lunghezza del telomero potrebbe costituire un indicatore della percentuale di proliferazione neoplastica.
Con il presente studio si intende valutare anche la lunghezza del telomero in pazienti pediatrici con trombocitosi ed eritrocitosi.

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Tipo di EPrint:Tesi di dottorato
Relatore:Randi, Maria Luigia
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE GERIATRICHE ED EMATOLOGICHE
Data di deposito della tesi:30 Gennaio 2013
Anno di Pubblicazione:30 Gennaio 2013
Parole chiave (italiano / inglese):MPN pediatriche / paediatric MPN trombocitemia essenziale / Essential Thrombocythemia eritrocitosi / Erythrocytosis
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:5797
Depositato il:16 Ott 2013 11:11
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