Uncovering metabolic profiles in Acute Myeloid Leukemia: from metabolic drivers to metabolic adaptations

Aysegül Erdem

    Research output: ThesisThesis fully internal (DIV)

    374 Downloads (Pure)

    Abstract

    Acute Myeloid Leukemia (AML) is a malignancy that occurs through accumulation and evolution of multiple genetic abnormalities resulting in malfunctioning hematopoietic stem cells. Our understanding of the molecular biology of cells that initiate and maintain leukemia and their crosstalk in the bone marrow microenvironment has enormously increased over the last two decades. Yet, due to the genetic and metabolic heterogeneity of leukemic stem cell populations among and even within AML patients, current therapy approaches often fail to cure this disease. Residual post-therapy leukemic stem cells have been shown to give rise to relapse of disease, and more insight needs to be obtained on the phenotype and biology of these cells.

    Altered metabolism is recognized as one of the hallmarks of cancer, and metabolic programs have been shown to control leukemic cell functions and impact on their chemosensitivity. For this reason, it is crucial to identify leukemic stem cell-specific abnormalities at the metabolome level in order to develop more effective treatment strategies for AML patients. In this thesis, we aimed to study major vulnerable molecular aberrancies in the metabolism of primary AML patients using quantitative proteomics, transcriptomic and functional metabolomics assays by comparing primary AML patient blasts to healthy stem and progenitors. During our studies, we identified several profound metabolic differences between specific AML subtypes carrying distinct genetic alterations. This allowed us to develop and monitor selective treatments in different AML subtypes using metabolic inhibitors against the distinct metabolic signatures, which was also evaluated in vivo in leukemic xenograft mouse models.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Schuringa, Jan Jacob, Supervisor
    • Huls, Gerwin, Supervisor
    Award date21-Mar-2022
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-6423-694-1
    DOIs
    Publication statusPublished - 2022

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