Dynamics of somatic mosaicism in the murine hematopoietic system

• Applicants: Dr. Alexander Gerbaulet; Professor Dr. Thomas Höfer
• Subject Area: Hematology, Oncology ; Bioinformatics and Theoretical Biology ; Developmental Biology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497777320

Cell clones harboring somatic mutations known as cancer drivers have now been found in many phenotypically normal tissues and accumulate with aging. Hematopoiesis has emerged as a paradigm of such somatic mosaicism; large hematopoietic stem cell (HSC) clones with leukemic driver mutations are frequently found in healthy elderly. These observations raise the question which cellular mechanisms counteract leukemogenesis, and whether there are early warning signs that these protective mechanisms are breaking down. A clue is provided by the recent observation, by us and others, that HSC in mice show a remarkable pattern of activity: While being quiescent for several months, HSCs rarely but reliably become active to spawn a multipotent progenitor (MPP). MPPs exhibit extensive self-renewal in vivo and maintain production of blood cells long-term even when HSCs are depleted. Hence, we hypothesize that the rare HSC output functions to prevent excessive accumulation of mutations in more rapidly dividing progenitors. To test this, we will make use of mouse models that: (i) allow the selective depletion of HSCs, (ii) genetically perturb epigenetic regulation by Tet2 loss-of-function, decreasing HSC output and increasing self-renewal, and (iii) globally increase mutation rate across the genome. We will quantify the accumulation of somatic mutations in single HSCs and progenitors as well as in bulk cells, yielding complementary information on mutation count in single cells and on the frequency distribution of somatic variants in sorted populations, respectively. Using mathematical approaches from population genetics, we will infer from these comprehensive data the clonal evolution of hematopoiesis during normal aging and in response to the perturbations. Moreover, we will reconstruct evolutionary paths to malignancy triggered by Tet2 loss-of-function and increased mutation rate. This project will yield unprecedented insight into somatic mosaicism in mice and origins of leukemogenesis. Given that myelodysplastic disorders in humans frequently give rise to acute leukemia, we expect that our findings will inform novel approaches at understanding, and early diagnosing, this transition to leukemia.

• DFG Programme: Research Grants