Somatic mutations and cell identity linked by Genotyping of Transcriptomes

Anna S. Nam, Kyu-Tae Kim, Ronan Chaligne, Franco Izzo, Chelston Ang, Justin Taylor, Robert M. Myers, Ghaith Abu-Zeinah, Ryan Brand, Nathaniel D. Omans, Alicia Alonso, Caroline Sheridan, Marisa Mariani, Xiaoguang Dai, Eoghan Harrington, Alessandro Pastore, Juan R. Cubillos-Ruiz, Wayne Tam, Ronald Hoffman, Raul Rabadan, Joseph M. Scandura, Omar Abdel-Wahab, Peter Smibert and Dan A. Landau ()
Additional contact information
Anna S. Nam: Weill Cornell Medicine
Kyu-Tae Kim: New York Genome Center
Ronan Chaligne: New York Genome Center
Franco Izzo: New York Genome Center
Chelston Ang: New York Genome Center
Justin Taylor: Memorial Sloan Kettering Cancer Center
Robert M. Myers: New York Genome Center
Ghaith Abu-Zeinah: Weill Cornell Medicine
Ryan Brand: New York Genome Center
Nathaniel D. Omans: New York Genome Center
Alicia Alonso: Weill Cornell Medicine
Caroline Sheridan: Weill Cornell Medicine
Marisa Mariani: Weill Cornell Medicine
Xiaoguang Dai: Oxford Nanopore Technologies
Eoghan Harrington: Oxford Nanopore Technologies
Alessandro Pastore: Memorial Sloan Kettering Cancer Center
Juan R. Cubillos-Ruiz: Weill Cornell Medicine
Wayne Tam: Weill Cornell Medicine
Ronald Hoffman: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Raul Rabadan: Columbia University Medical Center
Joseph M. Scandura: Weill Cornell Medicine
Omar Abdel-Wahab: Memorial Sloan Kettering Cancer Center
Peter Smibert: New York Genome Center
Dan A. Landau: New York Genome Center

Nature, 2019, vol. 571, issue 7765, 355-360

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1367-0

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