Errichiello, Santa (2015) Characterization Of The Bone Marrow Microenvironment That Provides Survival Signals Contributing To Therapy Failure In Patients With Leukemia. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Characterization Of The Bone Marrow Microenvironment That Provides Survival Signals Contributing To Therapy Failure In Patients With Leukemia.
Creators:
CreatorsEmail
Errichiello, Santaerrichiello@ceinge.unina.it
Date: 31 March 2015
Number of Pages: 71
Institution: Università degli Studi di Napoli Federico II
Department: Scienze Chimiche
Scuola di dottorato: Biotecnologie
Dottorato: Scienze biotecnologiche
Ciclo di dottorato: 27
Coordinatore del Corso di dottorato:
nomeemail
Sannia, Giovannisannia@unina.it
Tutor:
nomeemail
Pane, FabrizioUNSPECIFIED
Date: 31 March 2015
Number of Pages: 71
Uncontrolled Keywords: microenvironment, CML, therapy
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Area 05 - Scienze biologiche > BIO/12 - Biochimica clinica e biologia molecolare clinica
Area 06 - Scienze mediche > MED/15 - Malattie del sangue
Aree tematiche (7° programma Quadro): SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana
BIOTECNOLOGIE, PRODOTTI ALIMENTARI E AGRICOLTURA > Scienze della vita, biotecnologia e biochimica per prodotti e processi non-alimentari sostenibili
Date Deposited: 07 Apr 2015 08:01
Last Modified: 04 May 2016 01:00
URI: http://www.fedoa.unina.it/id/eprint/10375
DOI: 10.6092/UNINA/FEDOA/10375

Abstract

The importance of tumor microenvironment for cancer progression is becoming widely recognized in recent years. The Bone Marrow (BM) is a dynamic microenvironment with high concentration of growth factors and cytokines necessary for haematopoiesis, making it a highly permissive zone for cancer haematopoietic staminal cell homing and survival. It is possible that the same factors that modulate hematopoiesis promote leukemogenesis, enhance blast survival and make them resistant to treatment within the BM microenvironment. In the era of molecular target therapy, whereas Imatinib has shown a cumulative best complete cytogenetic response rate of 82% and an estimated event free survival at 8 years of 85%, several in vitro data have confirmed that Ph+ CD34+ progenitor cells crammed in BM niches are resistant to TKI treatments. We attempted to define BM microenvironment markers that nurture and determine stem cell fate in leukemia associated-niches. We treated Ph+ K562 cell lines and primary CD34+ BM cells derived from untreated CML patients with a dose range of TKIs (0-100µM) in the presence of a monolayer of human BM mesenchimal stromal cell line (HS-5) or HS5 conditioned media (HCM), to assess the role of BM niche in the regulation of TKI responsiveness. We demonstrated that BM stroma environment significantly protects K562 cell line from TKI-induced apoptosis. Indeed, we demonstrated that Half maximal inhibitory concentration (IC50) value (calculated on cell viability) of Imatinib, Nilotinib and Dasatinib significantly increased when leukemic cells are exposed to HS5 or HCM. Moreover, we prove that a significant TKI-resistance could be achieved also by Ph+ CD34+ primary CML cells exposed to HS5 or HCM. Taken together, these findings indicate that BM-derived stroma cell line produces a strong effect on the regulation of TKI responsiveness in Ph+ CML cells by both a direct cell-to-cell contact and exposition to soluble factors. Moreover, the observed TKI resistance is associated to a BCR-ABL independent STAT-3 activation leading to a significant down-modulation of apoptosis when either Ph+ cell line or primary CD34+ progenitor cells derived from patients with CML are treated with TKIs in the presence of a direct mesenchymal stroma cell interaction or exposition to SCM. Finally, I proved that JAK inhibitor Ruxolitinib, that inhibits STAT3 phosphorylation (a marker of JAK activity), synergizes with TKIs in the induction of apoptosis in CML primary cells. Indeed, compared with single agent treatment, exposure of CML cells to the combination of TKI and JAK inhibitor Ruxolitinib significantly decreased viability of CML cells and increased their apoptosis in vitro. Taken together, our data show that the rational drug combination of TKI and Ruxolitinib may enhance the eradication of primary human Ph+ cells homed in BM stroma niche.

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