Aging, hematopoietic stem cells, gene expression and clonality, cell by cell

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Aging is thought to contribute to aging-associated leukemia like myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Age-related clonal hematopoiesis (ARCH or simply CH) is defined as the gradual, clonal expansion of hematopoietic stem and progenitor cells (HSPCs) carrying specific, disruptive, and recurrent genetic variants without clear diagnosis of hematological malignancies. CH is regarded to be the initiating step for MDS and/or AML. Understanding how CH develops and why it is linked to aging is a prerequisite to design rationale approaches to target CH and thus to reduce the initiation of aging-associated MDS or AML. We propose to perform single cell sequencing (384 cells per individual donor) on HSCs, multi-potent progenitors (MPPs) and hematopoietic progenitor cells (HPCs) from young and older adults with SMART-Seq2 technology to apply novel, innovative analyses to determine true single nucleotide variants (SNVs, aka mutations) and gene expression profiles. Based on this data, we will determine clonality in hematopoiesis (HSCs, MPPs, HPCs and in BM) in individuals and among individuals to ultimately provide a comprehensive view at which step in hematopoiesis clonality develops and which genes are affected. We anticipate that the data and the analyses based on the data will become a highly valued resource for the international scientific community and will move the field significantly forward.