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Chiodin, Giorgia (2017) Chronic Lymphocytic Leukemia: analysis of microenvironmental influence on neoplastic clone survival and IgM signaling during Ibrutinib therapy. [Tesi di dottorato]

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Abstract (inglese)

Chronic Lymphocytic Leukemia (CLL) is characterized by the monoclonal expansion of mature CD19+/CD5+/CD23+ B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. Surface IgM (sIgM) signaling is key to CLL behavior and is a therapeutic target of the BTK-inhibitor Ibrutinib. SIgM levels and signaling capacity are variable in CLL and correlate with the behavior of the disease. In CLL, the microenvironment also plays an important role in disease support and progression. In this thesis two projects are presented: the analysis of the microenvironmental influence on neoplastic clone survival in different in vitro culture conditions, and the study of the effects that Ibrutinib in vivo therapy exerts on sIgM in CLL patients.
Mesenchymal Stromal Cells (MSCs), which represent the major component of the stromal microenvironment, were isolated from the marrow aspirate of CLL patients and co-cultured with leukemic cells. After 7 days, we observed a relevant extended survival of leukemic cells in respect to the B cells cultured alone, and the behavior of the neoplastic clones could be differently dependent on the signals coming from the stromal cells. MSCs were able to counteract the cytotoxic effect of Fludarabine/Cyclophosphamide in vivo administration, confirming the important role played by the microenvironment during therapy. However, the kinase inhibitors Ibrutinib and Bafetinib could induce apoptosis of leukemic cells co-cultured with MSCs, and inhibited CLL B cell CD49d-mediated adhesion and pseudoemperipolesis, suggesting that the new kinase inhibitors are effective in targeting the pro-survival cross-talk between leukemic lymphocytes and stromal cells.
In patients, Ibrutinib treatment induces a rapid redistribution of CLL cells into the blood. In this study, the expression and function of sIgM was analyzed in 12 CLL patients after 1 week of Ibrutinib therapy. At this time point, the expression of sIgM increased significantly (P=0.001), accompanied by full N-glycan maturation of sIgM heavy-chain, indicating recovery from antigen engagement. In addition, the sIgM levels correlated with increased sIgM-mediated SYK phosphorylation. The data suggest that Ibrutinib could prevent antigen encounter, thus favoring sIgM expression and maturation.

Abstract (italiano)

La leucemia linfatica cronica (LLC) e’ caratterizzata dall’accumulo di linfociti B maturi con fenotipo CD19+/CD5+/CD23+ nel sangue periferico, nel midollo osseo e nei tessuti linfatici. I segnali mediati dalle immunoglobuline M di superficie (sIgM) sono fondamentali per il comportamento dei linfociti di LLC, e sono divenuti target di inibitori chinasici come Ibrutinib. I livelli di sIgM e la capacita’ di mediare segnali intracellulari sono variabili nei cloni tumorali e si associano al comportamento della malattia. Inoltre, anche il microambiente tumorale ricopre un ruolo importante nel supporto e nella progressione della LLC. In questa tesi sono presentati due progetti: l’analisi dell’influenza del microambiente sulla sopravvivenza del clone neoplastico in diverse condizioni di coltura in vitro, e lo studio degli effetti della terapia con Ibrutinib su signalling e funzionalita’ delle sIgM in pazienti di LLC.
Nella prima parte dello studio, le cellule mesenchimali stromali (MSCs) sono state isolate da aspirati midollari da pazienti affetti da LLC e sono state poste in co-coltura con cellule B neoplastiche. Dopo 7 giorni di incubazione, abbiamo osservato un rilevante incremento della sopravvivenza delle cellule leucemiche poste in co-coltura con MSCs rispetto alle cellule poste in coltura singola; abbiamo osservato che cloni diversi mostrano comportamento diverso in termini di sopravvivenza, in base alle caratteristiche intrinseche dei cloni stessi. Le MSCs, inoltre, sono in grado di contrastare l’effetto citotossico della terapia Fludarabina/Ciclofosfamide quando somministrata in vivo in pazienti con LLC, a conferma dell’importante ruolo svolto dal microambiente. Tuttavia, i risultati ottenuti hanno mostrato che gli inibitori chinasici Ibrutinib e Bafetinib sono invece in grado di indurre apoptosi nelle cellule tumorali anche in presenza di MSCs e di inibirne l’adesione mediata da CD49d e la pseudemperipolesi, suggerendo che gli inibitori del signalling del BCR sono efficaci nel bloccare il cross-talk tra linfociti neoplastici e cellule stromali.
Nei pazienti affetti da LLC il trattamento con Ibrutinib induce una rapida ridistribuzione delle cellule tumorali nel sangue. In questo studio, l’espressione e la funzione delle sIgM e’ stata analizzata in 12 pazienti con LLC dopo 1 settimana di terapia con Ibrutinib. A questo time point, l’espressione di IgM sulla superficie delle cellule neoplastiche e’ risultata significativamente aumentata (P=0.001); allo stesso tempo abbiamo anche osservato un aumento della forma matura della catena pesante delle sIgM, indicativa di un mancato incontro con l’antigene. Inoltre, i risultati ottenuti hanno mostrato una correlazione tra l’incremento dei livelli di sIgM e l’aumentata fosforilazione di SYK mediata da IgM. I dati suggeriscono che Ibrutinib potrebbe prevenire l’incontro con l’antigene, favorendo quindi espressione e maturazione delle sIgM nelle cellule di LLC.

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Tipo di EPrint:Tesi di dottorato
Relatore:Facco, Monica
Dottorato (corsi e scuole):Ciclo 29 > Corsi 29 > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:28 Gennaio 2017
Anno di Pubblicazione:28 Gennaio 2017
Parole chiave (italiano / inglese):CLL, B cells, MSC, Ibrutinib, Bafetinib, kinase inhibitors, microenvironment
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/15 Malattie del sangue
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:10013
Depositato il:15 Nov 2017 09:40
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