Caruso, Simona (2017) The pluripotency transcription factor Nanog plays a potential role as a BCR/ABL independent mechanism of TKI resistance in Chronic Myeloid Leukemia. [Tesi di dottorato]

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: The pluripotency transcription factor Nanog plays a potential role as a BCR/ABL independent mechanism of TKI resistance in Chronic Myeloid Leukemia.
Autori:
AutoreEmail
Caruso, Simonasimocaruso@alice.it
Data: Maggio 2017
Numero di pagine: 91
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Medicina Clinica e Chirurgia
Dottorato: Terapie avanzate medico-chirurgiche
Ciclo di dottorato: 29
Coordinatore del Corso di dottorato:
nomeemail
Di Minno, Giovannigiovanni.diminno@unina.it
Tutor:
nomeemail
Pane, Fabrizio[non definito]
Data: Maggio 2017
Numero di pagine: 91
Parole chiave: CML, Nanog, TKI resistance
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/15 - Malattie del sangue
Depositato il: 27 Apr 2017 10:12
Ultima modifica: 14 Mar 2018 11:56
URI: http://www.fedoa.unina.it/id/eprint/11817
DOI: 10.6093/UNINA/FEDOA/11817

Abstract

Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disease characterized by a specific chromosomal translocation t(9;22) that gives rise to a fusion gene BCR-ABL1. The oncogenic product BCR-ABL1 is a constitutively active tyrosine kinase that promotes cell proliferation and inhibits apoptosis of the leukemic clone. In the era of target therapy, the treatment of CML patients in chronic phase (CML-CP) with tyrosine kinase inhibitors (TKIs) showed a substantially life expectancy improving. However, a large number of them develop drug intolerance or resistance and relapse after TKIs treatment. If on one hand, BCR-ABL1 dependent Imatinib resistance can be overcome by second or third generation TKIs, on the other hand, the molecular mechanisms that underlie BCR-ABL1 independent resistance are not well clarified. It is becoming evident that persistent leukemic stem cells (LCSs) can lead to disease relapse at the time of TKI withdrawal in a relevant portion of the patients. In this context, we sought to evaluate Nanog role in the regulation of CML cells response to TKI therapy. Nanog is an essential transcription factor involved in the regulatory networks that are responsible for stemness in embryonic pluripotent stem cells. Furthermore, functional studies have provided evidences that the expression levels of Nanog play crucial role in malignant diseases promoting tumorigenicity, invasiveness, and therapeutic resistance. We have observed a significant level of Nanog protein expression in Philadelphia positive (Ph+) K562 cells after Imatinib treatment whether compared to untreated control since 24 hours of treatment, with a persistence of expression at least until 72 hours. Moreover, we also have described a time-dependent up-regulation of Nanog protein in K562 Ph+ cell line treated with increasing doses not only of Imatinib (first generation TKI), but also of Nilotinib (second generation TKI), confirming the correlation between TKI treatment and Nanog overexpression. Moreover, we demonstrated that the Nanog protein overexpression is restricted to alive cells and persists after TKI withdrawal. The RT-qPCR analysis revealed that Nanog expression is modulated at transcriptional level after exposure to first and second generation TKIs showing a correlation with Nanog protein increasing. Furthermore, we proved that Nanog overexpression is independent from BCR-ABL1 activity; indeed, after Imatinib treatment, in K562 cell line, BCR-ABL1 expression was reduced, instead Nanog expression was increased. Finally, we evaluated Nanog expression in two cohorts of CML-CP patients at baseline treated with 1) Imatinib or 2) Nilotinib and we observed a significant up-regulation in Warning or Failure responder patients; contrariwise, Optimal responder patients showed a significant down-regulation of Nanog mRna expression. Taken together, these findings demonstrate the involvement of Nanog in TKI resistance in K562 Ph+ cell line and identify Nanog as a potential marker of molecular response in CML patients

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