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Exploring combined treatment strategies to target quiescent chronic myeloid leukemia (CML) stem cells

Burgos Espadinha, Daniel António

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Chronic myeloid leukemia (CML) was one of the first malignancies suggested to be driven by leukemic stem cells (LSCs) and currently serves as a disease model for stem cell based malignancies. The constitutively active BCR-ABL tyrosine kinase, created by a reciprocal translocation between chromosomes 22 and 9, drives progression of this leukemia and is thus an ideal target for drug design. Research has led to the development of the tyrosine kinase inhibitor (TKI) Imatinib, which selectively and potently inhibits the BCR-ABL kinase, leading to a rapid hematologic and cytogenetic response in most CML patients. However, following years of treatment with Imatinib, remaining residual LSCs can lead to a relapse of the disease on cessation of treatment, highlighting the need for a curative approach to eliminate both the bulk of leukemia as well as the LSCs. Quiescence has been proposed as a potential mechanism through which LSCs remain resistant to TKI treatment, and therefore pushing these cells into cycle may make them susceptible to TKI, leading to their eradication. Recently, our group has demonstrated that the cytokine Interferon-alpha (IFNα) can very efficiently drive quiescent hematopoietic stem cells (HSCs) into an active cell cycle. Here, we have investigated whether IFNα is also capable of activating quiescent BCR-ABL expressing LSCs. Furthermore, we have explored whether IFNα-induced activation makes LSCs more susceptible to Imatinib treatment and investigated the potential beneficial effect of a combined treatment with IFNα and Imatinib. To address these questions we used CML mouse models in which BCR-ABL expression is mainly targeted to the HSC population. Here we could demonstrate that upon IFNα exposure, quiescent LSCs enter an active cell cycle and proliferate similarly as HSCs. Furthermore, we have tested several treatment schemes for a combined treatment in our mouse models. Interestingly, the continuous administration of Imatinib together with pulsed exposures to IFNα led to a more significant reduction of the leukemic burden when compared to either of the treatments alone. Furthermore, we also investigated the influence of the leukemic cells on the behavior of wt cells in our CML mouse models. Here, we could show that leukemic cells induced an alteration of the wt cell population distributions in a way that mimic the leukemic compartment. This effect may be mediated by a leukemia-induced modification of the cytokine repertoire that we have also characterized in the leukemic BM. In addition, by examining the reconstitution ability of the wt cells that coexisted with the leukemic cells, we could show that exposure to a leukemic environment impairs the function of wt progenitors and HSCs. Taken together, our data indicate that a combined strategy of continuous TKI administration together with pulsed activation of LSCs through IFNα exposure is more advantageous than TKI alone and may thus avoid relapse of the disease by eradicating LSCs. Moreover, our data suggest that the presence of leukemic cells is detrimental for the wt cells, impairing the function of wt progenitors and HSCs.

Item Type: Dissertation
Supervisor: Trumpp, Prof. Dr. Andreas
Date of thesis defense: 18 December 2015
Date Deposited: 12 Jan 2016 08:10
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
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