Intercellular mitochondrial transfer in the bone marrow microenvironment of acute myeloid leukaemia and multiple myeloma

Marlein, Christopher (2018) Intercellular mitochondrial transfer in the bone marrow microenvironment of acute myeloid leukaemia and multiple myeloma. Doctoral thesis, University of East Anglia.

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Acute Myeloid Leukaemia (AML) and Multiple Myeloma (MM) are currently incurable malignancies which have devastating effects on patients who develop them. Chemotherapeutic regimens have remained largely unchanged over recent decades, it is therefore apparent that there is a need for novel therapeutic interventions. It is thought that these new treatments will come to fruition through a better understanding of the biological processes which underpin these diseases. Cancer cells have classically been thought to generate ATP through the non-mitochondrial based Warburg hypothesis, however it is becoming apparent that malignant cells are equally reliant on mitochondrial oxidative phosphorylation to fuel their rapid proliferation. Mitochondria were thought to remain in their somatic cell for their lifetime; however, ground-breaking research from the Gerdes laboratory has shown that mitochondria can move between somatic cells. In my thesis, I aimed to examine whether mitochondria were transferred between non-malignant bone marrow stromal cells (BMSC) and AML/MM cells.

Mitochondria were shown to move from BMSC to AML blasts and MM cells, this process enhanced the proliferation of these malignancies. AML-derived NOX2 superoxide was shown to stimulate mitochondrial biogenesis in BMSC, allowing mitochondria to move to AML blasts through tunnelling nanotubes. In the MM, it was found that CD38 expression on MM cells was able to form tunnelling nanotubes which facilitated the trafficking of mitochondria. Inhibition of NOX2 and CD38, in AML and MM respectively, reduced disease progression in vivo in part by reducing the quantity of mitochondria which move to the malignant cell. Furthermore, it was shown that AML/MM hijack this process from normal haematopoiesis as mitochondria move in vivo to haematopoietic stem cells in response to bacterial infection. Taken together I have presented a novel biological process in haematopoietic malignancies, which may be exploited to treat AML and MM.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Jennifer Whitaker
Date Deposited: 05 Mar 2019 10:22
Last Modified: 05 Mar 2019 10:22

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