Single-cell dissection of immune system aging and acute myeloid leukemia

Karakaslar, E.O.

doi:doi:10.60602/1887-4306748

Hematopoietic stem cells (HSCs) sustain lifelong blood production but accumulate somatic mutations with age, increasing the risk of myeloid malignancies such as acute myeloid leukemia (AML). This thesis investigates how aging and genetic alterations reshape the transcriptional and epigenetic landscape of hematopoiesis and how these changes can be leveraged for precision medicine.

Using bulk and single-cell multi-omics, functional experiments, and computational approaches, this work demonstrates that aging alters immune cell composition, reduces naïve T-cell populations, and promotes inflammatory programs, particularly through activation of the AP-1 transcriptional network in monocytes. It further shows that epigenetic interventions can expand the HSC pool, highlighting opportunities to improve stem cell transplantation and gene therapy.

In AML, the thesis reveals that transcriptional profiling captures disease heterogeneity beyond genetic...Show moreHematopoietic stem cells (HSCs) sustain lifelong blood production but accumulate somatic mutations with age, increasing the risk of myeloid malignancies such as acute myeloid leukemia (AML). This thesis investigates how aging and genetic alterations reshape the transcriptional and epigenetic landscape of hematopoiesis and how these changes can be leveraged for precision medicine.

Using bulk and single-cell multi-omics, functional experiments, and computational approaches, this work demonstrates that aging alters immune cell composition, reduces naïve T-cell populations, and promotes inflammatory programs, particularly through activation of the AP-1 transcriptional network in monocytes. It further shows that epigenetic interventions can expand the HSC pool, highlighting opportunities to improve stem cell transplantation and gene therapy.

In AML, the thesis reveals that transcriptional profiling captures disease heterogeneity beyond genetic classifications. Patients carrying identical genetic lesions can exhibit distinct cellular states, differentiation trajectories, and treatment responses, uncovering clinically relevant subgroups hidden within current diagnostic categories.

Together, these findings connect normal immune aging with leukemia development, identify age-associated biological vulnerabilities, and provide a framework for integrating molecular profiling into leukemia classification. This work advances our understanding of hematopoietic aging and supports the development of more personalized strategies for the diagnosis, prevention, and treatment of hematological malignancies.
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Single-cell dissection of immune system aging and acute myeloid leukemia