Chicken or Egg: Is Clonal Hematopoiesis Primarily Caused by Genetic or Epigenetic Aberrations?

Hematopoietic malignancies, including multiple myeloma, are associated with characteristic mutations and genetic instabilities that drive malignant transformation. On the other hand, tumor formation is also associated with drastic epigenetic aberrations, which can impact the genetic sequence. Therefore, the question arises if malignant transformation is primarily caused by genetic or epigenetic events. The tight connection of these processes becomes obvious by the fact that in several malignancies, as well as in age-related clonal hematopoiesis, mutations are particularly observed in epigenetic writers such as DNMT3A and TET2. On the other hand, specific epigenetic aberrations, so-called "epimutations," can mimic genomic mutations. In contrast to the genetic sequence, which remains relatively stable throughout life, the epigenome notoriously undergoes drastic changes in normal hematopoietic development and aging. It is conceivable that such epigenetic reorganization, e.g., in 3D chromatin conformation, paves the way for secondary chromosomal instabilities, which then result in tumor-specific genomic changes that further trigger disease progression. This scenario might explain the occurrence of tumor-specific mutations particularly in the elderly. Taken together, the causality dilemma is difficult to solve because genetic and epigenetic aberrations are interlinked during disease development. A better understanding of how the chromatin structure or 3D nuclear organization can evoke specific mutations might provide new perspectives for prevention, early diagnostics, and targeted therapy.