Open Access

Christina Ann Ortmann, Lena Dorsheimer, Khalil Abou-El-Ardat, Jennifer Hoffrichter, Birgit Aßmus, Halvard-Björn Bönig, Anica Scholz, Heike Pfeifer, Hans Martin, Tobias Schmid, Bernhard Brüne, Sebastian Scheich, Björn Steffen, Julia Riemann, Stella Hermann, Alexandra Dukat, Gesine Bug, Christian Hubertus Brandts, Sebastian Alexander Wagner, Hubert Serve, Michael A. Rieger

• Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.