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Raggi, Flavia (2018) HSP70/HSF1 axis has a role in the pathogenesis of Chronic Lymphocytic Leukemia and is a druggable target. [Ph.D. thesis]

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Abstract (italian or english)

Chronic Lymphocytic Leukemia (CLL) is a neoplastic disorder, characterized by the accumulation of clonal B lymphocytes due to an increased proliferation and the inability to reach programmed cell death. CLL is a heterogeneous disease with some patients asymptomatic, while others experience a more aggressive disorder, treatment failure and a poor overall survival. As a consequence, novel biological and cytogenetic features are crucial to predict patient’s prognosis, and the search for key molecules involved in the pathogenesis of the disease is still ongoing.
We previously performed a Reverse Phase Protein Array (RPPA) analysis for the identification of new proteins, which might contribute to the apoptosis resistance and the increased survival of CLL cells. We found the Heat Shock Protein of 70kDa (HSP70) significantly overexpressed in CLL cells with respect to normal controls. HSP70 is a molecular chaperone induced in response to several physiological and environmental insults, thus allowing cells to survive to otherwise lethal conditions. The main responsible of HSP70 transcription is the Heat Shock Factor 1 (HSF1), able to bind to DNA and to activate Heat Shock gene transcription in response to stress.
During this three-year PhD project, we were aimed at characterizing HSP70 and its major regulator, HSF1, in CLL cells.
We found HSP70 and HSF1 both overexpressed (138 CLL patients, 1.24±0.85 vs 32 healthy controls, 0.77±0.57; p<0.01; 85 CLL patients 0.81±0.77 vs 19 healthy controls, 0.30±0.36; p<0.01, respectively), correlated to poor prognosis and abnormally localized in the nucleus of CLL cells. We showed that the two protein levels were decreased, and positively correlated to each other (e.g. p<0.05; r=0.94), in patients responding to in vivo therapeutic regimens.
To better understand HSP70 and HSF1 role in CLL, we performed in vitro inhibition of these proteins using specific drugs (VER-155008, KRIBB11, zafirlukast, fisetin), which led to a dose-dependent apoptosis of leukemic cells from CLL patients (e.g. cell viability at 24h: CLL cells alone 63±14%, vs CLL cells + 15µM fisetin 35±19%, p<0.0001). Moreover, we demonstrated that fisetin was able to bypass the microenvironmental protection when neoplastic B cells were co-cultured with 15µM fisetin and MSCs (e.g. 30±17%, 25±19%, 26±15% without MSCs, and 32±14%, 35±23%, 33±22% with MSCs at 24, 48, 72h, respectively).
HSF1 is regulated by its interactions with molecular chaperones, and also by a fine balance of activatory and inhibitory phosphorylations. Since most of HSF1-phosphorylating molecules belong to two RAS-signalling pathways (PI3K/AKT/mTOR and RAF/MEK/ERK), taking advantage from our previous RPPA analysis, we correlated HSP70 to different proteins related to these signals. By a cluster analysis, we divided our patients in HSP70high and HSP70low, on the basis of HSP70 protein levels, demonstrating that the RAS pathway proteins are differently regulated in the two groups. For HSP70high patients, we developed a model based on high AKT-Ser473 levels, in which AKT-Ser473 inhibits GSK3a/b that, in turn, is unable to inhibit HSF1. On the other hand, HSP70low patients present high MEK1/2-Ser217/221 and ERK-Thr202/Tyr204, that negatively regulate HSF1. As a result, the activation of the PI3K/AKT/mTOR pathway leads to a higher expression of HSP70, while an activation of the RAF/MEK/ERK pathway results in HSP70 downregulation.
By RAS pathway inhibition, we validated our model for the aberrant regulation of HSP70/HSF1 axis in CLL. To this purpose, we used resveratrol, a natural polyphenol, able to inhibit AKT and to activate ERK. After 24h treatment with 40µM resveratrol, we observed a reduction in cell viability (61±18% of untreated cells vs 54±20%; p<0.01) with a decreased protein expression both for HSF1 and HSP70: 1.15±0.69 to 0.50±0.64, and from 1.13±0.69 to 0.54±0.35, respectively; p<0.01).
In conclusion, the HSP70 and HSF1 overexpression and correlation with resistance to therapy in CLL, together with the ability of fisetin to induce apoptosis in leukemic B cells bypassing the pro-survival stimuli of tumor microenvironment, represent a starting point for the development of new therapeutic strategies. Moreover, the study of resveratrol effects on leukemic B cells provides new insights on the cross-talk between HSP70/HSF1 axis and RAS signalling in CLL.

Abstract (a different language)

La Leucemia Linfatica Cronica (LLC) è una malattia neoplastica, caratterizzata dall'accumulo di linfociti B clonali proliferanti e resistenti alla morte cellulare programmata. Questa leucemia è una malattia eterogenea: alcuni pazienti possono essere asintomatici, mentre altri sperimentano un decorso più aggressivo. Di conseguenza, nuove informazioni biologiche e citogenetiche sono necessarie per prevedere la prognosi del paziente e per curare la malattia attraverso la ricerca di nuove molecole coinvolte nella sua patogenesi.
In precedenza, il nostro laboratorio aveva eseguito un'analisi di RPPA (Reverse Phase Protein Array) allo scopo di identificare nuove proteine coinvolte nella resistenza all'apoptosi e nella sopravvivenza delle cellule di LLC. Grazie a questo studio, abbiamo verificato che la Heat Shock Protein di 70kDa (HSP70) era significativamente sovraespressa nelle cellule di LLC rispetto ai controlli sani. HSP70 è uno chaperone molecolare indotto in risposta a numerosi insulti fisiologici e ambientali, che consente alle cellule di sopravvivere in condizioni altrimenti letali. Il principale responsabile della trascrizione di HSP70 è Heat Shock Factor 1 (HSF1), il quale, in risposta allo stress, è in grado di legarsi al DNA ed attivare la trascrizione dei geni dell’heat shock.
Durante questo progetto triennale di dottorato, ci siamo focalizzati sulla caratterizzazione di HSP70 e del suo principale regolatore, HSF1, nella LLC.
Abbiamo dimostrato che HSP70 e HSF1 sono sovraespresse (138 pazienti LLC, 1,24 ± 0,85 vs 32 controlli sani, 0,77 ± 0,57; p <0,01; 85 pazienti LLC 0,81 ± 0,77 vs 19 controlli sani, 0,30 ± 0,36; p <0,01, rispettivamente) e correlate a prognosi sfavorevole nella LLC. Abbiamo inoltre osservato che queste due proteine sono localizzate in modo anomalo nel nucleo delle cellule leucemiche. Nei pazienti che rispondevano a regimi terapeutici in vivo, abbiamo evidenziato una diminuzione dei livelli proteici di HSP70 e HSF1 e una correlazione positiva tra gli stessi (p <0,05; r = 0,94).
Per comprendere meglio il ruolo di HSP70 e HSF1 nella LLC, le abbiamo inibite in vitro utilizzando molecole specifiche (VER-155008, KRIBB11, zafirlukast, fisetina), che si sono rivelate in grado di indurre apoptosi nelle cellule leucemiche da pazienti con LLC (vitalità a 24 ore: solo cellule LLC 63 ± 14%, vs cellule LLC + fisetina 15μM 35 ± 19%, p <0,0001). Inoltre, abbiamo dimostrato che la fisetina era in grado di oltrepassare la protezione fornita dal microambiente quando le cellule B neoplastiche erano poste in co-coltura con MSC e fisetina 15μM (senza MSC: 30 ± 17%, 25 ± 19%, 26 ± 15%; con MSC: 32 ± 14%, 35 ± 23%, 33 ± 22% a 24, 48, 72 ore).
HSF1 non è regolato soltanto dalle sue interazioni con chaperoni molecolari, ma anche da un fine equilibrio tra fosforilazioni attivatorie e inibitorie. Poiché la maggior parte delle molecole che fosforilano HSF1 appartiene a due vie di segnalazione di RAS (PI3K/AKT/mTOR e RAF/MEK/ERK), sfruttando la nostra precedente analisi RPPA, abbiamo correlato HSP70 a diverse proteine appartenenti a questi pathway. Abbiamo diviso i nostri pazienti sulla base dei livelli di HSP70 in due gruppi: HSP70high e HSP70low, dimostrando che le proteine dei pathway di RAS sono regolate in modo diverso nei due gruppi. Per HSP70high abbiamo sviluppato un modello basato su elevati livelli di AKT-Ser473, che ha la capacità di inibire GSK3a/b che, a sua volta, non è più in grado di inibire HSF1. I pazienti HSP70low, invece, presentano elevati livelli di MEK1/2-Ser217/221 e ERK-Thr202/Tyr204, che regolano negativamente HSF1. Di conseguenza, l'attivazione del pathway PI3K/AKT/mTOR porta ad un'espressione più elevata di HSP70, mentre l'attivazione del pathway RAF/MEK/ERK determina una down-regolazione di HSP70.
Abbiamo convalidato il nostro modello per la regolazione aberrante dell'asse HSP70/HSF1 nella LLC inibendo alcune molecole dei pathway di RAS. A questo scopo, abbiamo usato il resveratrolo, un polifenolo naturale in grado di inibire AKT ed attivare ERK. Dopo 24 ore di trattamento con resveratrolo alla dose di 40μM, abbiamo osservato una riduzione della vitalità cellulare (61 ± 18% delle cellule non trattate contro 54 ± 20% di quelle trattate; p <0,01) ed una ridotta espressione proteica di HSF1 e HSP70 (da 1,15 ± 0,69 a 0,50 ± 0,64 e da 1,13 ± 0,69 a 0,54 ± 0,35, rispettivamente, p <0,01).
In conclusione, la sovraespressione di HSP70 e HSF1 e la loro correlazione con la resistenza alla terapia nella LLC, insieme alla capacità della fisetina di indurre apoptosi nelle cellule B leucemiche bypassando gli stimoli pro-sopravvivenza del microambiente tumorale, rappresentano un punto di partenza per lo sviluppo di nuove strategie terapeutiche. Inoltre, lo studio degli effetti del resveratrolo sulle cellule B leucemiche fornisce nuove informazioni sul cross-talk tra l'asse HSP70/HSF1 e la via del segnale di RAS nella LLC.

EPrint type:Ph.D. thesis
Tutor:Facco, Monica
Ph.D. course:Ciclo 31 > Corsi 31 > ONCOLOGIA CLINICA E SPERIMENTALE E IMMUNOLOGIA
Data di deposito della tesi:27 November 2018
Anno di Pubblicazione:27 November 2018
Key Words:Chronic Lymphocytic Leukemia, HSP70, HSF1 Leucemia Linfatica Cronica, HSP70, HSF1
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/15 Malattie del sangue
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:11395
Depositato il:07 Nov 2019 17:55
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