Unravelling the ontogeny of clonal hematopoiesis and functional consequences in the stem cell compartment

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Recently, it has been shown that clonal hematopoiesis, defined by the presence of a somatic hematologic cancer associated gene mutation, occurs in the peripheral blood of at least 10% of persons older than 65 years of age without any history of hematologic disorders. The presence of this common phenomenon constitutes a pre-malignant state which is associated with an increased risk of hematologic cancers and an increased overall mortality. Clonal hematopoiesis occurs in an age-related manner indicating a close connection between stem cell aging and the distinct gene mutations. All given data advocates for stem cell and/or progenitor cell involvement as origin of clonal hematopoiesis. In line with this hypothesis, we and others were able to show that some of the affected gene mutations can be identified in hematopoietic stem cells (HSCs) of patients suffering from various hematologic malignancies including acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL), indicating that these mutations are very likely disease initiating events in hematologic neoplasms. The overall goal of the proposed project is to comprehensively characterize clonal hematopoiesis and study its functional impact in individuals without any history of hematologic disorders. Additionally, we aim to unravel genetic aberrations and oncogenic networks that drive malignant transformation at both early and late steps of hematopoietic differentiation. To achieve this we propose the following specific aims: Aim 1: To study the mutation burden across the hematopoietic differentiation tree and define the molecular ontogeny of clonal hematopoiesis. Aim 2: To study the functional consequences of gene mutations in mature cell fractions. Aim 3: To identify mutation-specific differentiation properties in the stem cell compartment of individuals with clonal hematopoiesis and modelling functional consequences of gene mutations during stem cell aging in human cord blood systems.