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Cited by 226

The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.

Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level

Chen, Jiahao, Kao, Yun-Ruei, Sun, Daqian, Todorova, Tihomira I., Reynolds, David, Narayanagari, Swathi-Rao, Montagna, Cristina, Will, Britta, Verma, Amit, Steidl, Ulrich·2019·Nature Medicine
DOI 10.1038/s41591-018-0267-4PMC PMC6436966
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Abstract

Myelodysplastic syndromes (MDS) frequently progress to acute myeloid leukemia (AML); however, the cells leading to malignant transformation have not been directly elucidated. As progression of MDS to AML in humans provides a biological system to determine the cellular origins and mechanisms of neoplastic transformation, we studied highly fractionated stem cell populations in longitudinal samples of patients with MDS who progressed to AML. Targeted deep sequencing combined with single-cell sequencing of sorted cell populations revealed that stem cells at the MDS stage, including immunophenotypically and functionally defined pre-MDS stem cells (pre-MDS-SC), had a significantly higher subclonal complexity compared to blast cells and contained a large number of aging-related variants. Single-cell targeted resequencing of highly fractionated stem cells revealed a pattern of nonlinear, parallel clonal evolution, with distinct subclones within pre-MDS-SC and MDS-SC contributing to generation of MDS blasts or progression to AML, respectively. Furthermore, phenotypically aberrant stem cell clones expanded during transformation and stem cell subclones that were not detectable in MDS blasts became dominant upon AML progression. These results reveal a crucial role of diverse stem cell compartments during MDS progression to AML and have implications for current bulk cell–focused precision oncology approaches, both in MDS and possibly other cancers that evolve from premalignant conditions, that may miss pre-existing rare aberrant stem cells that drive disease progression and leukemic transformation. High-resolution sequencing of longitudinal patient samples reveals subclonal mutational diversity in the stem cell compartment driving parallel evolution patterns in acute myeloid leukemia progression.

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Research works printed but not linked: 2

  1. Garrison, E. & Marth, G. Haplotype-based variant detection from short-read sequencing. Preprint at https://arxiv.org/abs/1207.3907 (2012). · arXiv
  2. Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Preprint at https://arxiv.org/abs/1303.3997 (2013). · arXiv

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Metadata

Authors
Chen, J., Kao, Y.-R., Sun, D., Todorova, T. I., Reynolds, D., Narayanagari, S.-R., Montagna, C., Will, B., Verma, A., & Steidl, U.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-12-03
Volume
25
Issue
1
Pages
103-110
ISSN
  • 1078-8956
  • 1546-170X
DOI
10.1038/s41591-018-0267-4
PMC
PMC6436966
Cited by
226
References
59
Language
en
Update notices
correction (2018-12-19)
Licence
www.springer.com/tdm (tdm)

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