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

IF 11.5 Q1 HEMATOLOGY Blood Cancer Discovery Pub Date : 2024-11-01 DOI:10.1158/2643-3230.BCD-23-0138
Livius Penter, Nicoletta Cieri, Katie Maurer, Marwan Kwok, Haoxiang Lyu, Wesley S Lu, Giacomo Oliveira, Satyen H Gohil, Ignaty Leshchiner, Caleb A Lareau, Leif S Ludwig, Donna S Neuberg, Haesook T Kim, Shuqiang Li, Lars Bullinger, Jerome Ritz, Gad Getz, Jacqueline S Garcia, Robert J Soiffer, Kenneth J Livak, Catherine J Wu
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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.

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利用线粒体 DNA 突变追踪异体造血细胞移植后罕见的单个供体和受体免疫细胞和白血病细胞。
结合追踪克隆进化和嵌合细胞表型,可以检测出与治疗后(包括异基因造血干细胞移植(HSCT)后)反应相关的关键细胞群。我们证明,在造血干细胞移植后复发时,线粒体DNA(mtDNA)突变与体细胞核DNA突变共同进化,为监测这些细胞群提供了灵敏的手段。此外,通过单细胞ATAC和选择抗原测序(ASAP-seq)检测mtDNA突变,不仅能同时确定供体和受体细胞,还能确定它们的表型,检测频率为0.1-1%。最后,通过整合 mtDNA 突变、表面标记和染色质可及性图谱,可以从正常免疫细胞中分辨出白血病群体的表型,从而为移植后白血病复发治疗后的残余供体源性移植和短期克隆进化提供新的见解。随着吞吐量的提高,我们预计未来基于单细胞测序的移植后监测将发展成为指导临床决策的有力方法。
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
期刊最新文献
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