Clonal hematopoiesis with and mutations impairs regeneration in autologous stem cell transplant recipients.

Niels Weinhold, Carsten Müller-Tidow, George S Vassiliou, Sascha Dietrich, Andreas Trumpp, Sascha Laier, Petra Pavel, Birgit Besenbeck, Hartmut Goldschmidt, Marc S Raab, Patrick Stelmach, Rumyana Proynova, Nora Liebers, Maike Janssen, Christian Rohde, Muxin Gu, Margarete A Fabre, Sandra Sauer, Sarah Richter

Journal: Haematologica 2023;108(12):3308-3320

PMID: 37381752

Free Full Text on PubMed Central View on PubMed

Abstract

Clonal hematopoiesis (CH) is an age-related condition driven by stem and progenitor cells harboring recurrent mutations linked to myeloid neoplasms. Currently, potential effects on hematopoiesis, stem cell function and regenerative potential under stress conditions are unknown. We performed targeted DNA sequencing of 457 hematopoietic stem cell grafts collected for autologous stem cell transplantation (ASCT) in myeloma patients and correlated our findings with high-dimensional longitudinal clinical and laboratory data (26,510 data points for blood cell counts/serum values in 25 days around transplantation). We detected CHrelated mutations in 152 patients (33.3%). Since many patients (n=54) harbored multiple CH mutations in one or more genes, we applied a non-negative matrix factorization (NMF) clustering algorithm to identify genes that are commonly co-mutated in an unbiased approach. Patients with CH were assigned to one of three clusters (C1-C3) and compared to patients without CH (C0) in a gene specific manner. To study the dynamics of blood cell regeneration following ASCT, we developed a time-dependent linear mixed effect model to validate differences in blood cell count trajectories amongst different clusters. The results demonstrated that C2, composed of patients with DNMT3A and PPM1D single and co-mutated CH, correlated with reduced stem cell yields and delayed platelet count recovery following ASCT. Also, the benefit of maintenance therapy was particularly strong in C2 patients. Taken together, these data indicate an impaired regenerative potential of hematopoietic stem cell grafts harboring CH with DNMT3A and PPM1D mutations.

Address: Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM, gGmbH), Heidelberg.; Department of Medicine V, Heidelberg University Hospital, Heidelberg.; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Haematology, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R/D, AstraZeneca, Cambridge.; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Haematology, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge.; Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg.; Stem Cell Laboratory, Institute of Clinical Transfusion Medicine and Cell Therapy Heidelberg GmbH, Heidelberg.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM, gGmbH), Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg.; Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL), Heidelberg.; Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL), Heidelberg. [email protected].

DOI: 10.3324/haematol.2023.282992

Link outs

Free resources

Full Text Sources:

Miscellaneous:

https://assays.cancer.gov/non-CPTAC-1105

MeSH Terms: Humans, Clonal Hematopoiesis, Hematopoietic Stem Cell Transplantation, Transplantation, Autologous, Hematopoiesis, Mutation, Regeneration, Protein Phosphatase 2C