Somatic mutations and cell identity linked by Genotyping of Transcriptomes Journal Article

   

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.
Article Title:	Somatic mutations and cell identity linked by Genotyping of Transcriptomes
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. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Journal Title:	Nature
Volume:	571
Issue:	7765
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2019-07-18
Start Page:	355
End Page:	360
Language:	English
DOI:	10.1038/s41586-019-1367-0
PROVIDER:	scopus
PMCID:	PMC6782071
PUBMED:	31270458
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85068540502&doi=10.1038%2fs41586-019-1367-0&partnerID=40&md5=0ad5d90104e87fc232f9888eae48cf27
Notes:	Article -- Export Date: 2 August 2019 -- Source: Scopus

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