Chromosomal instability upregulates interferon in acute myeloid leukemia.
Bone Marrow Cells
/ drug effects
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Cells, Cultured
Chromosomal Instability
Chromosome Segregation
DNA Damage
Humans
Interferons
/ genetics
Karyotype
Leukemia, Myeloid, Acute
/ genetics
Mutagens
/ toxicity
Protein Kinase Inhibitors
/ toxicity
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Protein-Tyrosine Kinases
/ antagonists & inhibitors
Up-Regulation
CIN
Mps1
aneuploidy
cell cycle checkpoints
mitosis
mitotic checkpoint
spindle assembly checkpoint
Journal
Genes, chromosomes & cancer
ISSN: 1098-2264
Titre abrégé: Genes Chromosomes Cancer
Pays: United States
ID NLM: 9007329
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
05
11
2019
revised:
08
06
2020
accepted:
09
06
2020
pubmed:
20
6
2020
medline:
19
8
2021
entrez:
20
6
2020
Statut:
ppublish
Résumé
Chromosome instability (CIN) generates genetic and karyotypic diversity that is common in hematological malignancies. Low to moderate levels of CIN are well tolerated and can promote cancer proliferation. However, high levels of CIN are lethal. Thus, CIN may serve both as a prognostic factor to predict clinical outcome and as a predictive biomarker. A retrospective study was performed to evaluate CIN in acute myeloid leukemia (AML). Chromosome mis-segregation frequency was correlated with clinical outcome in bone marrow core biopsy specimens from 17 AML cases. Additionally, we induced chromosome segregation errors in AML cell lines with AZ3146, an inhibitor of the Mps1 mitotic checkpoint kinase, to quantify the phenotypic effects of high CIN. We observed a broad distribution of chromosome mis-segregation frequency in AML bone marrow core specimens. High CIN correlated with complex karyotype in AML, as expected, although there was no clear survival effect. In addition to CIN, experimentally inducing chromosome segregation errors by Mps1 inhibition in AML cell lines causes DNA damage, micronuclei formation, and upregulation of interferon stimulated genes. High levels of CIN appear to be immunostimulatory, suggesting an opportunity to combine mitotic checkpoint inhibitors with immunotherapy in treatment of AML.
Identifiants
pubmed: 32557940
doi: 10.1002/gcc.22880
pmc: PMC7597364
mid: NIHMS1636164
doi:
Substances chimiques
Cell Cycle Proteins
0
Mutagens
0
Protein Kinase Inhibitors
0
Interferons
9008-11-1
Protein-Tyrosine Kinases
EC 2.7.10.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
TTK protein, human
EC 2.7.12.1
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
627-638Subventions
Organisme : NCI NIH HHS
ID : P30 CA014520
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008692
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA234904
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007899
Pays : United States
Informations de copyright
© 2020 Wiley Periodicals LLC.
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