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Galla, Luisa (2013) "New implications for the LKB1/AMPK pathway: regulation of apoptosis and circadian rhythm". [Tesi di dottorato]

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Abstract (inglese)

Acute Lymphoblastic Leukemia (ALL), the most common pediatric cancer, is an aggressive malignancy of lymphopoietic cells characterized by a clonal proliferation of blast cells originated from lymphoid precursors arrested at early stages of differentiation. Nowadays the introduction of risk-directed treatment and intensified cure protocols has improved the outcome of ALL pediatric patients. Although current therapies achieve five-year event-free survival rate of about 80% in children, the rest of patients experience treatment resistance and risk of early relapse. In order to develop new additional therapeutic supports and to assemble specific and personalized therapies, improving drug response and reducing drug toxicity, it is extremely important to identify novel therapeutic targets and new prognostic biomarkers on leukemic cells.
To pursue this aim, we first explored through Reverse Phase Protein Arrays (RPPA) the phosphoproteomic profile of B-cell precursor (BCP)-ALL pediatric patients. This technique represents a powerful tool to profile protein pathways activation in order to identify novel diagnostic and prognostic biomarkers and new therapeutics targets. RPPA approach leads to measure the activation levels/phosphorylation of large numbers of signalling proteins and to identify critical interactions within the protein network. This is a potential starting point for drug development and/or design of individual therapy regimens.
The principal aim of my PhD research was the discovery of new candidate biomarkers and therapeutic targets involved in the leukemic process starting from the study of the phosphoproteomic profiles of 118 BCP-ALL pediatric patients through RPPA. We screened the expression/activation of 92 different proteins/phophoproteins part of key signalling “hubs”. Correlation of signalling activation with clinical response and known genetic information enabled us to identify new protein pathway biomarkers that, when validated in larger clinical sets, could be used for patients stratification and targeted therapy trials. In detail, we observed an increased activation/expression of several pathways involved in cell proliferation in patients with a clinical poor phenotype. First, MLL-rearranged leukemia patients revealed BCL-2 hyperphosphorylation caused by AMPK activation, indicating that AMPK could be responsible of apoptosis inhibition in these patients and thus it could be considered as a new potential therapeutic target. Second, in patients with poor clinical response to Prednisone we observed the up-modulation of LCK activity with respect to patients with good response. This tyrosine-kinase can be down-modulated with clinically used inhibitors that could be considered for further studies as a new additional therapy for Prednisone-resistant patients. Further we also found an association between high levels of CYCLIN E and relapse incidence. Moreover, CYCLIN E is more expressed in patients with early relapse, who usually show an unfavourable prognosis. We decided to first explore in deep the functional significance of AMPK activation in MLL-rearranged patients. We showed that the AMPK pathway contributes directly to the survival of MLL-rearranged BCP-ALL cells and AMPK can be considered a new druggable target in MLL-rearranged leukemias. Indeed its inhibition, using a commercial inhibitor (Compound C), induces cell death through the intrinsic apoptosis pathway in both cell lines and primary samples. Moreover, Compound C is able to synergize with drugs commonly used in pediatric ALL therapy.
The second aim was thus to study in deep the AMPK principal activator that was also observed to be hyperphosphorylated in the previous study, LKB1. LKB1 was found to be overexpressed in MLL-rearranged leukemia at protein level, but not at mRNA level. Its specific silencing brought cell cycle block at S phase and apoptosis. Very interestingly we also found that LKB1 is hyperphosphorylated in cells during mitosis and is localized at centrosome. This result opens the possibility that LKB1 could play a key role in the control of cell cycle through regulation of elongation and stability of microtubules probably following the AMPK-MRLC pathway. Moreover LKB1 probably controls also DNA damage in MLL-rearranged leukemia, indeed its inhibition induces mitotic catastrophe.
LKB1 is a master kinase and has broad known functions, even in cellular metabolism and circadian rhythm. The third aim of my PhD was thus focused on the role played by LKB1 in circadian rhythm. We report that LKB1 is a key factor in circadian control, interacting with clock-proteins. LKB1 is able to regulate clock-proteins phosphorylation, function and localization in the cell in a circadian manner. Therefore, a comprehensive understanding of the molecular links that connect LKB1 and the circadian clock could provide therapeutic benefit against cancer. For example, specific LKB1 inhibitors or activators can be more effective in the treatment of cancer if administered at a particular time of the day (chronotherapy).
In my PhD thesis I showed that identification and functional studies of new aberrant molecular players involved in cancer will be useful in order to highlight the connection between these novel markers and the goal to discover more effective patient-tailored treatments.

Abstract (italiano)

La Leucemia linfoblastica acuta (LAL), il tumore pediatrico più diffuso, è una patologia delle cellule linfopoietiche caratterizzata da una proliferazione clonale di blasti originati dai precursori linfoidi bloccati a stati differenziativi precoci. Ad oggi un miglioramento della prognosi dei pazienti affetti da LAL è stato portato dall’introduzione di trattamenti differenziati sulla base del rischio di ricaduta e da protocolli di cura più intensi. Le terapie attualmente usate permettono di ottenere una sopravvivenza dell'€™80% a 5 anni dalla diagnosi, tuttavia esiste ancora circa un 20% di pazienti che presenta rischio di ricaduta precoce e resistenza alla terapia. Risulta dunque fondamentale identificare nuovi target terapeutici e biomarcatori delle cellule leucemiche al fine di sviluppare trattamenti di supporto innovativi e di individuare terapie più specifiche, migliorando la risposta alle terapie e riducendone la loro tossicità. Per perseguire questo obiettivo, per prima cosa tramite la tecnica di Reverse Phase Protein Arrays (RPPA) abbiamo mappato il profilo fosfoproteomico di pazienti pediatrici BCP-LAL. Questa tecnica rappresenta uno strumento potente per studiare il profilo proteico delle vie di trasduzione del segnale con lo scopo di identificare nuovi marker prognostici e target terapeutici. Con la metodica degli RPPA è possibile misurare il livello di attivazione/espressione di un ampio numero di proteine di segnale e di identificare alterazioni nei punti chiave dei network cellulari. Questo risulta essere un punto di partenza potenziale per lo sviluppo di nuovi farmaci e/o l'€™ideazione di nuovi regimi terapeutici.
Lo scopo principale del mio dottorato di ricerca è stato la scoperta di nuovi biomarcatori e target terapeutici coinvolti nel processo leucemico partendo dallo studio del profilo fosfoproteomico di 118 pazienti pediatrici BCP-LAL attraverso la tecnica di RPPA.
Abbiamo analizzato i livelli di espressione/attivazione di 92 differenti proteine/fosfoproteine di segnalazione chiave. La correlazione sulle vie di trasduzione attivate con la risposta alla terapia e con le caratteristiche genetiche dei pazienti ci ha permesso l’identificazione nuovi biomarcatori che, una volta validati in un gruppo allargato di campioni di LAL-B, potranno permettere una migliore stratificazione dei pazienti e potranno essere usati per lo sviluppo di cure paziente-specifiche.
In particolare, in pazienti a prognosi infausta, abbiamo osservato un aumento dell’attivazione/espressione di diverse vie di trasduzione del segnale coinvolte nella proliferaziione cellulare. In primo luogo, pazienti leucemici con traslocazione del gene MLL presentano l’iperfosforilazione di BCL-2 conseguente all’attivazione di AMPK, indicando che AMPK possa essere responsabile dell’inibizione dell’apoptosi in questi pazienti e quindi potrebbe essere un nuovo target terapeutico. Il secondo risultato osservato è una up-modulazione dell'€™attività di LCK nei pazienti con scarsa risposta al trattamento con Prednisone. Questa tirosina-chinasi potrebbe essere down-modulata tramite l’utilizzo di inibitori utilizzati in clinica e, quindi, potrebbe essere considerata per ulteriori studi al fine di identificare terapie addizionali per i pazienti resistenti al Prednisone. Da questa analisi fosfoproteomica è emersa, inoltre, un’associazione tra gli elevati livelli di CICLINA E e l’incidenza di ricaduta. In aggiunta la CICLINA E è risultata essere maggiormente espressa in pazieni con ricaduta precoce, generalmente associata ad una prognosi sfavorevole.
Successivamente abbiamo approfondito, come prima cosa, il significato funzionale dell’attivazione di AMPK nei pazienti con riarrangiamento del gene MLL. Abbiamo dimostrato che il pathway di AMPK contribuisce direttamente alla sopravvivenza delle cellule BCP-LAL MLL-riarrangiate, suggerendo AMPK come nuovo target terapeutico per questo tipo di leucemia. Infatti l’inibizione di AMPK, tramite l’utilizzo del suo inibitore commerciale (Compound C), porta a morte cellulare attraverso la via intrinseca di apoptosi sia nelle linee cellulari sia in colture cellulari primarie. Inoltre il Compound C ha azione sinergica con farmaci utilizzati in clinica per la terapia di pazienti pediatrici LAL.
Il secondo scopo del mio dottorato di ricerca è stato quello di focalizzarmi su LKB1, principale attivatore di AMPK, risultato essere anch’esso iperfosforilato nello studio di proteomica. LKB1 è stato trovato overespresso a livello proteico, ma non a livello di mRNA nelle leucemie con riarrangiamento del gene MLL. Il suo silenziamento specifico porta ad un blocco del ciclo cellulare in fase S e conseguente apoptosi.
Molto interessante è stata la scoperta che LKB1 risulta essere iperfosforilato nelle cellule in mitosi, con localizzazione centrosomica. Questo data apre la possibilità che LKB1 possa avere un ruolo chiave nella regolazione del ciclo cellulare tramite la regolazione dell’allungamento e della stabilità dei microtubuli, probabilmente attraverso il pathway AMPK-MRLC. In aggiunta LKB1 potrebbe avere un ruolo anche nel controllo del danno al DNA nelle leucemie con riarrangiamento del gene MLL, in quanto la sua inibizione porta a catastrofe mitotica.
LKB1 è una chinasi molto importante con funzioni note diffuse anche nel metabolismo cellulare e nel ritmo circadiano. Il terzo scopo del mio dottorato di ricerca è stato focalizzare lo studio del ruolo di LKB1 nel ritmo circadiano. Abbiamo scoperto che LKB1 gioca un ruolo chiave nel controllo circadiano, interagendo con le proteine clock.
LKB1, infatti, è in grado di fosforilare le proteine circadiane, regolandone funzione e localizzazione cellulare in modo circadiano.
Una compresione globale del collegamento molecolare che collega LKB1 e il sistema circadiano può portare a benefici nella terapia tumorale. Per esempio, specifici inibitori o attivatori di LKB1 potrebbero essere più efficaci nella terapia tumorale se somministrati in un particolare momento del giorno (cronoterapia).
Nella corso del mio dottorato ho potuto dimostrare che l'€™identificazione e lo studio funzionale di nuovi biomarcatori aberranti coinvolti nei tumori, possono essere utilizzati per sottolineare il collegamento tra questi con lo scopo ultimo di scoprire nuove efficaci terapie pazienti-specifiche

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Tipo di EPrint:Tesi di dottorato
Relatore:Accordi, Benedetta
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > EMATOONCOLOGIA, IMMUNOLOGIA E GENETICA
Data di deposito della tesi:29 Gennaio 2013
Anno di Pubblicazione:29 Gennaio 2013
Parole chiave (italiano / inglese):Acute Lymphoblastic Leukemia, AMPK, LKB1, circadian rhythm
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:5699
Depositato il:15 Ott 2013 10:35
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