The DOI matches its Crossref record; 92 of the 92 references it cites were found in a registry or an index.
Somatic mutations and cell identity linked by Genotyping of Transcriptomes
Open accessPublished version of a preprint
Abstract
Defining the transcriptomic identity of malignant cells is challenging in the absence of surface markers that distinguish cancer clones from one another, or from admixed non-neoplastic cells. To address this challenge, here we developed Genotyping of Transcriptomes (GoT), a method to integrate genotyping with high-throughput droplet-based single-cell RNA sequencing. We apply GoT to profile 38,290 CD34+ cells from patients with CALR-mutated myeloproliferative neoplasms to study how somatic mutations corrupt the complex process of human haematopoiesis. High-resolution mapping of malignant versus normal haematopoietic progenitors revealed an increasing fitness advantage with myeloid differentiation of cells with mutated CALR. We identified the unfolded protein response as a predominant outcome of CALR mutations, with a considerable dependency on cell identity, as well as upregulation of the NF-κB pathway specifically in uncommitted stem cells. We further extended the GoT toolkit to genotype multiple targets and loci that are distant from transcript ends. Together, these findings reveal that the transcriptional output of somatic mutations in myeloproliferative neoplasms is dependent on the native cell identity.
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“We further incorporated cell hashing 24 that enabled multiplexing baseline and IFNa-treated samples into the same scRNA-seq reactions via time-point specifying barcoded antibodies, to obviate technical batch effects between serial samples ( Fig. 1b ).”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [24]
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“we incorporated time-point specifying barcoded antibodies 24 to combine serial samples from the same individuals into a single experiment to remove technical batch effects”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [24]
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Metadata
- Authors
- Nam, A. S., Kim, K.-T., Chaligne, R., Izzo, F., Ang, C., Taylor, J., Myers, R. M., Abu-Zeinah, G., Brand, R., Omans, N. D., Alonso, A., Sheridan, C., Mariani, M., Dai, X., Harrington, E., Pastore, A., Cubillos-Ruiz, J. R., Tam, W., Hoffman, R., Rabadan, R., Scandura, J. M., Abdel-Wahab, O., Smibert, P., & Landau, D. A.
- Affiliations
- New York Genome Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Weill Cornell Medicine (US)
- Oxford Nanopore Technologies (United Kingdom) (GB)
- Tisch Cancer Institute (US)
- Corresponding author
- Landau, Dan A.
- ORCID
- Venue
- Nature
- Published
- 2019-07-03
- Volume
- 571
- Issue
- 7765
- Pages
- 355-360
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6782071
- OpenAlex
- W2954384525
- Cited by
- 333
- References
- 92
- Citations by year
- 2026: 35 · 2025: 54 · 2024: 59 · 2023: 41 · 2022: 44 · 2021: 49 · 2020: 36 · 2019: 13
- FWCI
- 11.74
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Burroughs Wellcome Fund
- Brigham and Women's Hospital
- National Institutes of Health (1dp2ca239065-01, 5r01ca229902-05, UL1TR002384)
- Stand Up To Cancer
- National Heart, Lung, and Blood Institute (R01HL145283, P01HL053762)
- National Cancer Institute (DP2-CA239065, U54CA193313, R01-CA229902, P30CA008748, P01CA108671)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Hematology › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- somatic mutations, cell identity, CALR mutation, myeloproliferative neoplasms, hematopoiesis, unfolded protein response, NF-κB signaling, myeloid differentiation, clonal fitness, single-cell RNA sequencing, droplet-based sequencing
- MeSH terms
- Animals, Cell Line, Clone Cells, Endoribonucleases, Genotype, Hematopoiesis, Hematopoietic Stem Cells, Humans, Models, Molecular, Mutation, Myeloproliferative Disorders, Neoplasms, Neoplastic Stem Cells, NF-kappa B, Protein Serine-Threonine Kinases, Sequence Analysis, RNA, Antigens, CD34, Calreticulin, Cell Proliferation, Mice, Primary Myelofibrosis, Unfolded Protein Response, Single-Cell Analysis, High-Throughput Nucleotide Sequencing, Transcriptome
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