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Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia

Giustacchini, A; Thongjuea, S; Barkas, N; Woll, PS; Povinelli, BJ; Booth, CAG; Sopp, P; ... Mead, AJ; + view all (2017) Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nature Medicine , 23 (6) pp. 692-702. 10.1038/nm.4336. Green open access

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Abstract

Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.

Type: Article
Title: Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/nm.4336
Publisher version: http://dx.doi.org/10.1038/nm.4336
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Cell Biology, CHRONIC MYELOGENOUS LEUKEMIA, GENE-EXPRESSION ANALYSIS, PRIMITIVE HEMATOPOIETIC-CELLS, ABL TYROSINE KINASE, RNA-SEQ, PROGENITOR CELLS, HETEROGENEITY, REMISSION, IMATINIB, IMPACT, Cancer stem cells, Chronic lymphocytic leukaemia, Transcriptomics
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10044333
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