Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
07
08
2018
accepted:
23
10
2018
pubmed:
5
12
2018
medline:
11
5
2019
entrez:
5
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30510255
doi: 10.1038/s41591-018-0267-4
pii: 10.1038/s41591-018-0267-4
pmc: PMC6436966
mid: NIHMS1510456
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
103-110Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL139487
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA166429
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK105134
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA217092
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230756
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013330
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103961
Pays : United States
Commentaires et corrections
Type : ErratumIn
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