Exploring novel targeted therapeutic strategies against Acute Myeloid Leukemia cells based on inhibition of bromodomain proteins and CDC20 activity

Bruno, Samantha (2020) Exploring novel targeted therapeutic strategies against Acute Myeloid Leukemia cells based on inhibition of bromodomain proteins and CDC20 activity, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Oncologia, ematologia e patologia, 32 Ciclo.
Documenti full-text disponibili:
[img] Documento PDF (English) - Accesso riservato fino a 31 Dicembre 2022 - Richiede un lettore di PDF come Xpdf o Adobe Acrobat Reader
Disponibile con Licenza: Salvo eventuali più ampie autorizzazioni dell'autore, la tesi può essere liberamente consultata e può essere effettuato il salvataggio e la stampa di una copia per fini strettamente personali di studio, di ricerca e di insegnamento, con espresso divieto di qualunque utilizzo direttamente o indirettamente commerciale. Ogni altro diritto sul materiale è riservato.
Download (15MB) | Contatta l'autore

Abstract

Acute myeloid leukemia (AML) is a haematological malignancies arising from the accumulation of undifferentiated myeloid progenitors with an uncontrolled proliferation. The genomic landscape of AML revealed that the disease is characterized by high level of heterogeneity and is subjected to clonal evolution driven by selective pressure of chemotherapy. In this study, we investigated the therapeutic effects of the inhibition of BRD4 and CDC20 in vitro and ex vivo. We demonstrated that inhibition of BRD4 with GSK1215101A in AML cell lines was effective under hypoxia. It induced the activation of antioxidant response both, at transcriptomic and metabolomic levels, driven by enrichment of NRF2 pathway under normoxic and hypoxic condition. Moreover, the combined treatment with Omaveloxolone, a drug inducing NRF2 activation and NF-κB inhibition, potentiated the effects on apoptosis and colony forming capacity of stem progenitor cells. Lastly, gene expression profiling data revealed that combination treatment induced major changes in genes related to cell cycle, together with enrichment of cell differentiation pathways and negative regulation of WNT, in normoxia and hypoxia. Regarding CDC20, we observed its up-regulation in AML patients. Treatment with two different inhibitors, Apcin and proTAME, was effective in primary AML cells and in AML cell lines, through induction of apoptosis and mitotic arrest. The lack of correlation between proliferation markers and CDC20 levels in AML cell subpopulations supports the idea of alternative CDC20 functions, independent from its essential role during mitosis. CDC20-KD experiments conducted in AML cell lines revealed a mild effect on apoptosis induction, but no significant change in cell cycle progression. In summary, these results allowed the identification of a new strategy combination to improve the effects of BRD4 inhibition on LSC residing in the BM hypoxic niche, and provide some new evidence regarding the potential role of CDC20 as a new target for AML treatment.

Abstract
Tipologia del documento
Tesi di dottorato
Autore
Bruno, Samantha
Supervisore
Dottorato di ricerca
Ciclo
32
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
Acute myeloid leukemia, cell cycle, bromodomain proteins, CDC20.
URN:NBN
Data di discussione
26 Marzo 2020
URI

Altri metadati

Gestione del documento: Visualizza la tesi

^