Abstract
Lineage-tracing methods have enabled characterization of clonal dynamics in complex populations, but generally lack the ability to integrate genomic, epigenomic and transcriptomic measurements with live-cell manipulation of specific clones of interest. We developed a functionalized lineage-tracing system, ClonMapper, which integrates DNA barcoding with single-cell RNA sequencing and clonal isolation to comprehensively characterize thousands of clones within heterogeneous populations. Using ClonMapper, we identified subpopulations of a chronic lymphocytic leukemia cell line with distinct clonal compositions, transcriptional signatures and chemotherapy survivorship trajectories; patterns that were also observed in primary human chronic lymphocytic leukemia. The ability to retrieve specific clones before, during and after treatment enabled direct measurements of clonal diversification and durable subpopulation transcriptional signatures. ClonMapper is a powerful multifunctional approach to dissect the complex clonal dynamics of tumor progression and therapeutic response.
| Original language | English |
|---|---|
| Pages (from-to) | 758-772 |
| Number of pages | 15 |
| Journal | Nature Cancer |
| Volume | 2 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2021 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding
We acknowledge S. Pollock, L. Nguyen, H. Lyon and C. Patterson for expert project management. We thank C. Hahn, I. Leschiner and B. Persaud for excellent input on human sequencing analysis. We acknowledge support from the National Institutes of Health (5R21CA212928, 5R01CA226258 to A.B.; and 3P01CA206978-03S1, 1U10CA180861-01, 1P01CA206978-01 to C.J.W.). C.J.W. is a Scholar of the Leukemia and Lymphoma Society and C.G. is a Scholar through the American Society of Hematology MMSAP Program and the F31 Diversity Individual Predoctoral Fellowship program through the NCI. E.B. is a recipient of the University of Texas at Austin Provost’s Graduate Excellence Fellowship and the F.M. Jones & H.L. Bruce Endowed Graduate Fellowship. K.J. is grateful for support through a National Science Foundation Graduate Research Fellowship (1610403). B.A.K. was supported by a long-term EMBO fellowship (ALTF 14-2018). We thank the Dana-Farber Flow Cytometry Core, the Broad Institute Walk-Up Sequencing Core and the Genome Sequencing and Analysis Facility at the University of Texas at Austin for their services. All scRNA-seq workflows were conducted in the Translational Immunogenomics Laboratory at the Dana-Farber Cancer Institute. C.J.W. holds equity in BioNTech Inc. and receives research funding from Pharmacyclics. C.J.W. and D.N. have been consultants for H3 Biomedicine and received research funding from Celgene. G.G. receives research funds from IBM and Pharmacyclics and is an inventor of several bioinformatics-related patents, including related to MuTect and ABSOLUTE. All other authors declare no competing interests.
| Funders | Funder number |
|---|---|
| BioNTech Inc. | |
| University of Texas at Austin Provost | |
| National Science Foundation | 1610403 |
| National Institutes of Health | 3P01CA206978-03S1, 5R01CA226258, 1U10CA180861-01 |
| Foundation for the National Institutes of Health | |
| National Cancer Institute | R21CA212928 |
| American Society of Hematology | |
| European Molecular Biology Organization | ALTF 14-2018 |
| Leukemia and Lymphoma Society | |
| Celgene |
