Deciphering Critical Changes in the Methylome of Hematopoietic Stem Cells in Age-related Clonal Hematopoiesis and Myeloid Leukemogenesis

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One of the risk factors for developing acute myeloid leukemia (AML) is higher age. Considering that in the Western world, individuals aged 65 and older, are expected to survive approximately another 20 years, AML has a devastating impact on the survival of this age group. One of the key questions has been, and still is, which precise mechanisms lead to the steep increase in AML in the elderly. Several independent reports have demonstrated that aging is associated with the development of clonal hematopoiesis and that so called “age-related clonal hematopoiesis” (ARCH) significantly increases the probability of affected individuals to develop hematological neoplasias. These clinical implications have led to the proposal of a new disorder called “clonal hematopoiesis of indeterminate potential” (CHIP), which describes healthy individuals carrying mutations in genes known to be recurrently mutated in hematological malignancies. Importantly, CHIP is associated with mutations in epigenetic modifiers. In our proposal we hypothesize that there are critical changes in the DNA methylome between young versus aged HSCs derived from non-clonal hematopoiesis, aged HSCs from clonal hematopoiesis and LSCs from elderly patients with AML carrying mutations known to drive clonal hematopoiesis. First data indicate age-dependent global DNA methylation patterns from young to old. In the upcoming funding period, we will link global DNA methylation profiling with transcriptomes in the individual samples by RNA-Seq. We will furthermore characterize the transcriptome and methylome of clonal versus non-clonal HSCs by single cell sequencing and extend this analysis to primary AML samples characterized by a mosaique of leukemic stem cells and residual HSCs with and without age-related mutations. These data will be complemented by functional analyses, testing the role of candidate genes such as homeobox genes on development of CHIP in vivo.