Tracking Rare Single Donor and Recipient Immune and Leukemia Cells after Allogeneic Hematopoietic Cell Transplantation Using Mitochondrial DNA Mutations

Combined tracking of clonal evolution and chimeric cell phenotypes could enable detection of the key cellular populations associated with response following therapy, including after allogeneic hematopoietic stem cell transplantation (HSCT). We demonstrate that mitochondrial DNA (mtDNA) mutations coevolve with somatic nuclear DNA mutations at relapse post-HSCT and provide a sensitive means to monitor these cellular populations. Furthermore, detection of mtDNA mutations via single-cell assay for transposase-accessible chromatin with select antigen profiling by sequencing (ASAP-seq) simultaneously determines not only donor and recipient cells but also their phenotype at frequencies of 0.1% to 1%. Finally, integration of mtDNA mutations, surface markers, and chromatin accessibility profiles enables the phenotypic resolution of leukemic populations from normal immune cells, thereby providing fresh insights into residual donor-derived engraftment and short-term clonal evolution following therapy for post-transplant leukemia relapse. As throughput evolves, we envision future development of single-cell sequencing-based post-transplant monitoring as a powerful approach for guiding clinical decision-making. Significance: mtDNA mutations enable single-cell tracking of leukemic clonal evolution and donor-recipient origin following allogeneic HSCT. This provides unprecedented insight into chimeric cellular phenotypes of early immune reconstitution, incipient relapse, and quality of donor engraftment with immediate translational potential for future clinical post-transplant monitoring and decision-making.

Authors

Institutions

Publication Details

Journal
Blood Cancer Discovery
Published
2024-09-05
DOI
https://doi.org/10.1158/2643-3230.bcd-23-0138
Citations
6
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
1.71

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Tracking Rare Single Donor and Recipient Immune and Leukemia Cells after Allogeneic Hematopoietic Cell Transplantation Using Mitochondrial DNA Mutations

Jacqueline Suen Garcia, Shuqiang Li, Gad A. Getz, Donna Neuberg et al.
6 citations
Blood Cancer Discovery
Cancer Genomics and Diagnostics
1.71
article

Tracking Rare Single Donor and Recipient Immune and Leukemia Cells after Allogeneic Hematopoietic Cell Transplantation Using Mitochondrial DNA Mutations

Jacqueline Suen Garcia, Shuqiang Li, Gad A. Getz, Donna Neuberg, Giacomo Oliveira, Jerome Ritz, Marwan Kwok, Lars Bullinger, Livius Penter, Haesook T. Kim, Catherine J. Wu, Katie Maurer, Caleb A. Lareau, Kenneth J. Livak, Ignaty Leshchiner, Robert J. Soiffer, Haoxiang Lyu, Leif S. Ludwig, Nicoletta Cieri, Wesley S. Lu, Satyen H. Gohil
article en
6 citations

Abstract

Combined tracking of clonal evolution and chimeric cell phenotypes could enable detection of the key cellular populations associated with response following therapy, including after allogeneic hematopoietic stem cell transplantation (HSCT). We demonstrate that mitochondrial DNA (mtDNA) mutations coevolve with somatic nuclear DNA mutations at relapse post-HSCT and provide a sensitive means to monitor these cellular populations. Furthermore, detection of mtDNA mutations via single-cell assay for transposase-accessible chromatin with select antigen profiling by sequencing (ASAP-seq) simultaneously determines not only donor and recipient cells but also their phenotype at frequencies of 0.1% to 1%. Finally, integration of mtDNA mutations, surface markers, and chromatin accessibility profiles enables the phenotypic resolution of leukemic populations from normal immune cells, thereby providing fresh insights into residual donor-derived engraftment and short-term clonal evolution following therapy for post-transplant leukemia relapse. As throughput evolves, we envision future development of single-cell sequencing-based post-transplant monitoring as a powerful approach for guiding clinical decision-making. Significance: mtDNA mutations enable single-cell tracking of leukemic clonal evolution and donor-recipient origin following allogeneic HSCT. This provides unprecedented insight into chimeric cellular phenotypes of early immune reconstitution, incipient relapse, and quality of donor engraftment with immediate translational potential for future clinical post-transplant monitoring and decision-making.

Blood Cancer DiscoveryVol. 5(6)
Broad Institute (US), University College Hospital (GB), Memorial Sloan Kettering Cancer Center (US), University College London Hospitals NHS Foundation Trust (GB), Harvard University (US), Max Delbrück Center (DE), Humboldt-Universität zu Berlin (DE), Kettering University (US), Dana-Farber Cancer Institute (US), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), University College London (GB), Massachusetts Institute of Technology (US), Charité - Universitätsmedizin Berlin (DE), University of Birmingham (GB)
Conquer Cancer Foundation, Bristol-Myers Squibb, Leukemia and Lymphoma Society, American Society of Clinical Oncology, Dana-Farber/Harvard Cancer Center, Cancer Research UK, Deutsche Forschungsgemeinschaft, Else Kröner-Fresenius-Stiftung, Deutsche Krebshilfe, Berlin Institute of Health, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute
Peace, Justice and strong institutions
Openalex Percentile: Top 15%
Cancer Genomics and Diagnostics
1.71
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.