Blood count abnormalities and evolution of clonal hematopoiesis

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    Somatic mutations accumulate in hematopoietic stem or progenitor cells with advancing age and may confer a selective growth advantage resulting in clonal expansion. So-called clonal hematopoiesis is proposed to represent an early stage of myeloid malignancy, especially in the context of peripheral cytopenia. The work in this thesis focuses on a better understanding of clonal hematopoiesis and its relation to phenotypic changes in the hematopoietic system. Large-scale sensitive sequencing was applied to blood samples of older individuals from the population-based Lifelines cohort, focusing on those with blood count abnormalities. By including sequential samples we studied the dynamics of mutated clones over time. While both phenomena frequently occur with ageing, clonally expanded somatic mutations did not necessarily have a relationship with blood count abnormalities. We report on specific mutational patterns of potential clinical importance in the context of anemia, thrombocytopenia, thrombocytosis, erythrocytosis, monocytosis and for the oldest old. We studied the co-occurrence of somatic gene mutations and mosaic loss of the Y-chromosome, another frequent clonal event in ageing males. We further evaluated the spectrum and consequences of clonal hematopoiesis in patients with mobilization failure for autologous cell transplantation. Finally, we provide a comprehensive overview of clonal evolution in the general population. Based on longitudinal sequencing data of 3359 individuals, we revealed gene-specific patterns of clonal expansion, mutation acquisition, and risk of progression to overt hematological malignancy. Altogether, this thesis helps to distinguish high-risk patterns of clonal hematopoiesis and clinically relevant malignancy pre-stages in the context of ageing and blood count abnormalities.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    Begeleider(s)/adviseur
    • Huls, Gerwin, Supervisor
    • Jansen, J.H. , Supervisor, Externe Persoon
    • de Graaf, Aniek O., Co-supervisor, Externe Persoon
    Datum van toekenning18-jan.-2024
    Plaats van publicatie[Groningen]
    Uitgever
    DOI's
    StatusPublished - 2024

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