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Zonta, Francesca (2015) Ruolo anti-apoptotico della tirosin-chinasi Lyn nella leucemia linfatica cronica a cellule B. [Ph.D. thesis]

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Abstract (italian or english)

B-chronic lymphocytic leukemia (B-CLL) is the commonest leukemia in the Western world and is characterized by the clonal expansion of small CD5+ B lymphocytes in the pheripheral blood, bone marrow and lymphoid organs, due to defective apoptosis. One of the crucial factors for the survival of B-CLL cells is the anomalous activity of a few enzymes such as the lipide kinase PI3K, the Ser/Thr kinase PKC and the tyrosine-kinases Syk and Lyn. My research focus was Src family kinase Lyn, which is overexpressed, constitutively active and delocalized in the cytosol within an aberrant multiprotein complex, in association with the molecular chaperone Hsp90, which in turn accounts for the high level of tyrosine-phosphorylation, ultimately contributing to the cancer phenotype of B-CLL cells.
The aim of my PhD work was to identify Lyn’s cytosolic substrates potentially involved in the apoptosis resistance mechanisms observed in leukemia cells.
Using biochemical and biomolecular methods as well as a bioinformatics approach, two potential substrates of Lyn were identified, namely the cysteine protease caspase-8 and the protein phosphatase-2A (PP2A).
Firstly, we established that in B-CLL, the inactive zymogen of caspase-8, procaspase-8, is phosphorylated at Tyr380 by the cytosolic pool of Lyn, which brings about its inhibition and its structural rearrangements in a dymeric cytosolic form. The phosphorylation of Tyr380 of caspase-8 is abolished by the use of both the Lyn inhibitor dasatinib and the Hsp90 inhibitor geldanamycin, the latter of which also leads to the disassembly of the aberrant cytosolic complex and the drop in the Lyn’s cytosolic activity, resulting in the caspase-dependent apoptosis.
Secondly, we verified that Lyn negatively affects the activity of one of the key factors in the modulation of cell survival signals, PP2A. Phosphorylation of the catalytic subunit of PP2A at Tyr307 causes inhibition of the phosphatase activity not only per se but also strengthening the interaction of PP2A with its cellular inhibitor SET, which is also overexpressed in B-CLL cells. As a result, PP2A is stably preserved in an inhibited form, which contributes to the persistence of prosurvival signals, in particular those mediated by the serine/threonine kinase Akt. Moreover, to identify new compounds able to activate PP2A in order to contrast survival signals in B-CLL, we tested fingolimod (FTY720), which is already known as a PP2A activator, currently in use in the treatment of multiple sclerosis and recently emerging as a pro-apoptotic factor in different types of cancer cells. Notably, the mechanism of action consists in the ability of fingolimod to bind to SET and hence remove this cellular inhibitor of PP2A from its catalytic subunit. Since this drug is used as an immunosuppressive agent, by virtue of its provoking the degradation of the sphingosine-1-phosphate receptor, and shows cardiovascular side effects, it might prove unsuitable in a more complex therapeutic strategy. Therefore, fingolimod structural analogues which could not interfere with the sphingosine receptors, but could still destabilize the PP2A/SET complex were designed and synthesized. One of these compounds, MP07-66, showed an effectiveness similar to fingolimod, as to both the ability to disrupting the PP2A/SET complex and inhibit the protein kinase Akt, this latter being vital in preserving the survival signals. This compound also was able to induce apoptosis in leukemia cells, which effect was further enhanced by the combination with dasatinib by a synergistic mechanism, further confirming the role of phosphorylation in the stability of PP2A/SET.
In conclusion, this work identifies PP2A and Caspase 8 as substrates of the cytosolic aberrant activity of Lyn, confirming the key role of this tyrosine kinase in supporting multiple anti-apoptotic signals in the B-CLL. The molecular mechanisms of apoptosis resistance here identified may be potential targets in the development of new therapies for clinical use.

Abstract (a different language)

La leucemia linfatica cronica a cellule B (LLC-B) è la forma più comune di leucemia nell’adulto ed è caratterizzata dall’accumulo di piccoli linfociti B CD5+ nel sangue periferico, nel midollo osseo e negli organi linfatici, dovuto sia a un aumento della proliferazione, che a un difetto dei meccanismi di morte cellulare programmata. Tra i fattori che contribuiscono alla sopravvivenza del linfocita neoplastico un ruolo fondamentale svolge l’attività anomala di diversi enzimi con attività fosfotransferasica che modulano le principali vie di segnalazione intracellulare, tra cui la lipide chinasi PI3K, la serina/treonina chinasi PKC, e le tirosin-chinasi Syk e Lyn. L’attività di ricerca svolta durante il mio dottorato si è concentrata sulla Src chinasi Lyn, la quale in questa patologia risulta sovra-espressa, iperattiva e delocalizzata nel citosol come componente di un complesso multiproteico aberrante. All’interno di questo complesso, Lyn è associata al chaperone molecolare Hsp90, il quale la preserva in conformazione attiva, così contribuendo all’elevata tirosin-fosforilazione basale tipica della LLC-B.
Lo scopo della mia indagine è stato identificare le molecole substrato dell’anomala attività di Lyn, potenzialmente coinvolte nei fenomeni di resistenza all’apoptosi dei cloni leucemici. Grazie all’applicazione di metodi biochimici e biomolecolari, nonché a un approccio bioinformatico, abbiamo identificato due substrati proteici di Lyn, la proteasi caspasi 8 e la proteina fosfatasi 2A (PP2A).
In primo luogo, abbiamo dimostrato che nelle cellule B di LLC, la procaspasi 8, zimogeno della caspasi 8, è fosforilata in Tyr380 ad opera di Lyn citosolico; tale fosforilazione comporta non solo l’inibizione dell’attività caspasica ma anche il riarrangiamento strutturale della proteasi stessa, che nei cloni leucemici localizza nel citosol in forma dimerica. Tale inibizione viene rimossa usando sia inibitori di Lyn, come il dasatinib, sia inibitori di Hsp90, come geldanamicina, quest’ultimo provocando la rottura del complesso citosolico e quindi il calo dell’attività di Lyn e in ultima analisi attivando le vie apoptotiche estrinseca ed intrinseca.
In secondo luogo, abbiamo verificato che Lyn esercita un controllo negativo su uno dei fattori chiave della modulazione dei segnali che regolano la sopravvivenza cellulare, la serina/treonina fosfatasi PP2A. I nostri dati indicano l’esistenza di un meccanismo d’inibizione dell’attività fosfatasica di PP2A, che dipende sia dalla fosforilazione come tale in Tyr307 della subunità catalitica, ma anche dalla stabilizzazione dell’interazione della fosfatasi con il suo inibitore proteico cellulare SET, il quale è anch’esso sovra-espresso nelle cellule di LLC-B. La formazione di questo complesso stabile mantiene la fosfatasi in uno stato inattivo contribuendo quindi alla persistenza dei segnali di sopravvivenza mediati in particolar modo dalla serina/treonina chinasi Akt.
Inoltre, allo scopo di individuare nuove molecole in grado di riattivare PP2A e quindi utili a contrastare i segnali di sopravvivenza delle cellule leucemiche, abbiamo verificato l’utilità di un noto attivatore di PP2A, il fingolimod (FTY720), già impiegato nella sclerosi multipla e ultimamente rivelatosi efficace nel causare la morte cellulare in vari tipi di modelli di neoplasia. Il meccanismo di azione risiede nella capacità di rimuovere l’inibitore SET dalla subunità catalitica di PP2A. Questo composto, tuttavia, possedendo attività immunosoppressiva a causa dell’induzione della degradazione del recettore della sfingosina ma anche effetti collaterali a carico del sistema cardio-vascolare, può rivelarsi inadeguato nell’ottica di una più complessa strategia terapeutica in campo oncologico. Quindi sono stati sviluppati degli analoghi strutturali che non interferissero con il recettore della sfingosina ma destabilizzassero il complesso della PP2A fosforilata e SET. In questo modo è stato identificato un composto (MP07-66), con un’efficacia sovrapponibile al fingolimod sia nel disgregare il complesso che nell’inibire la protein chinasi Akt, fondamentale nel preservare i segnali di sopravvivenza. Inoltre tale composto era in grado di indurre apoptosi su cellule leucemiche, il quale effetto veniva incentivato dalla presenza di dasatinib con meccanismo sinergico, ulteriormente confermando il ruolo della fosforilazione nella stabilità del complesso PP2A/SET.
In conclusione, questo lavoro identifica PP2A e caspasi 8 quali substrati dell’attività citosolica aberrante di Lyn, confermando il ruolo chiave di questa chinasi nel supportare i molteplici segnali anti-apoptotici presenti nella LLC-B. I meccanismi molecolari di resistenza all’apoptosi qui identificati possono costituire dei potenziali bersagli per lo sviluppo di nuove terapie ad uso clinico.

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EPrint type:Ph.D. thesis
Tutor:Brunati, Anna Maria
Ph.D. course:Ciclo 27 > scuole 27 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE GERIATRICHE ED EMATOLOGICHE
Data di deposito della tesi:02 February 2015
Anno di Pubblicazione:02 February 2015
Key Words:Leucemia Linfatica Cronica; Protein Tirosin-chinasi Lyn; Apoptosi; Caspasi 8; Protein fosfatasi-2A/ Chronic Lymphocytic Leukemia; Protein Tyrosine kinase Lyn; Apoptosis; Caspase 8; Protein Phospatase-2A
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/15 Malattie del sangue
Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:7845
Depositato il:10 Nov 2015 13:02
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