State-Transition Analysis of Time-Sequential Gene Expression Identifies Critical Points That Predict Development of Acute Myeloid Leukemia.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 08 2020
01 08 2020
Historique:
received:
19
02
2020
revised:
06
04
2020
accepted:
12
05
2020
pubmed:
18
5
2020
medline:
18
12
2020
entrez:
17
5
2020
Statut:
ppublish
Résumé
Temporal dynamics of gene expression inform cellular and molecular perturbations associated with disease development and evolution. Given the complexity of high-dimensional temporal genomic data, an analytic framework guided by a robust theory is needed to interpret time-sequential changes and to predict system dynamics. Here we model temporal dynamics of the transcriptome of peripheral blood mononuclear cells in a two-dimensional state-space representing states of health and leukemia using time-sequential bulk RNA-seq data from a murine model of acute myeloid leukemia (AML). The state-transition model identified critical points that accurately predict AML development and identifies stepwise transcriptomic perturbations that drive leukemia progression. The geometry of the transcriptome state-space provided a biological interpretation of gene dynamics, aligned gene signals that are not synchronized in time across mice, and allowed quantification of gene and pathway contributions to leukemia development. Our state-transition model synthesizes information from multiple cell types in the peripheral blood and identifies critical points in the transition from health to leukemia to guide interpretation of changes in the transcriptome as a whole to predict disease progression. SIGNIFICANCE: These findings apply the theory of state transitions to model the initiation and development of acute myeloid leukemia, identifying transcriptomic perturbations that accurately predict time to disease development.
Identifiants
pubmed: 32414754
pii: 0008-5472.CAN-20-0354
doi: 10.1158/0008-5472.CAN-20-0354
pmc: PMC7416495
mid: NIHMS1596190
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Comment
Langues
eng
Sous-ensembles de citation
IM
Pagination
3157-3169Subventions
Organisme : NCI NIH HHS
ID : K08 CA201591
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA205247
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA250046
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA221709
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141379
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK097837
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178387
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentOn
Informations de copyright
©2020 American Association for Cancer Research.
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