Ihlow Jana, Penter Livius, Vuong Lam Giang, Bischoff Philip, Obermayer Benedikt, Trinks Alexandra, Blau Olga, Behnke Anke, Conrad Thomas, Morkel Markus, Wu Catherine J, Westermann Jörg, Bullinger Lars, von Brünneck Ann-Christin, Blüthgen Nils, Horst David, Praktiknjo Samantha D
Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Department of Hematology, Oncology and Cancer Immunology, Campus Virchow Clinic, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
Department of Hematology, Oncology and Cancer Immunology, Campus Virchow Clinic, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany; Department of Medical Oncology, Dana-Faber Cancer Institute, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
Med. 2025 Apr 11;6(4):100548. doi: 10.1016/j.medj.2024.11.001. Epub 2024 Dec 6.
Distinguishing donor- vs. recipient-derived myelodysplastic neoplasm (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is challenging and has direct therapeutical implications.
Here, we took a translational approach that we used in addition to conventional diagnostic techniques to resolve the origin of MDS in a 38-year-old patient with acquired aplastic anemia and evolving MDS after first allo-HSCT. Specifically, we used single-cell transcriptional profiling to differentiate between donor- and recipient-derived bone marrow cells and established a strategy that additionally allows identification of cells carrying the MDS-associated U2AF1 variant.
The patient exhibited mixed donor chimerism combined with severely reduced erythropoiesis and dysplastic morphology within the granulocytic and megakaryocytic lineage along with the MDS-associated U2AF1 mutation in the bone marrow. Single-cell transcriptional profiling together with targeted enrichment of the U2AF1-specific locus further revealed that, while the immune compartment was mainly populated by donor-derived cells, myelopoiesis was predominantly driven by the recipient. Additionally, concordant with recipient-derived MDS, we found that U2AF1-mutated cells were exclusively recipient derived with X but not Y chromosome-specific gene expression.
Our study highlights the clinical potential of integrating high-resolution single-cell techniques to resolve complex cases for personalized treatment decisions.
The study was funded by intramural resources of the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health.
