Downregulation of MTSS1 in acute myeloid leukemia is associated with a poor prognosis, chemotherapy resistance, and disease aggressiveness.
Animals
Anthracyclines
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Biomarkers, Tumor
/ genetics
Cell Cycle Proteins
/ genetics
Cytarabine
/ administration & dosage
Daunorubicin
/ administration & dosage
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Leukemic
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mice, Inbred C57BL
Microfilament Proteins
/ genetics
Neoplasm Proteins
/ genetics
Prognosis
Protein-Tyrosine Kinases
/ genetics
Survival Rate
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
17
08
2020
accepted:
11
03
2021
revised:
19
02
2021
pubmed:
31
3
2021
medline:
1
1
2022
entrez:
30
3
2021
Statut:
ppublish
Résumé
Despite recent approval of targeted drugs for acute myeloid leukemia (AML) therapy, chemotherapy with cytosine arabinoside and anthracyclines remains an important pillar of treatment. Both primary and secondary resistance are frequent and associated with poor survival, yet the underlying molecular mechanisms are incompletely understood. In previous work, we identified genes deregulated between diagnosis and relapse of AML, corresponding to therapy naïve and resistant states, respectively. Among them was MTSS1, whose downregulation is known to enhance aggressiveness of solid tumors. Here we show that low MTSS1 expression at diagnosis was associated with a poor prognosis in AML. MTSS1 expression was regulated by promoter methylation, and reduced by cytosine arabinoside and the anthracycline daunorubicin. Experimental downregulation of MTSS1 affected the expression of numerous genes. It induced the DNA damage response kinase WEE1, and rendered human AML cell lines more resistant to cytosine arabinoside, daunorubicin, and other anti-cancer drugs. Mtss1 knockdown in murine MLL-AF9-driven AML substantially decreased disease latency, and increased leukemic burden and ex vivo chemotherapy resistance. In summary, low MTSS1 expression represents a novel factor contributing to disease aggressiveness, therapy resistance, and poor outcome in AML.
Identifiants
pubmed: 33782537
doi: 10.1038/s41375-021-01224-2
pii: 10.1038/s41375-021-01224-2
pmc: PMC8478650
mid: EMS119145
doi:
Substances chimiques
Anthracyclines
0
Biomarkers, Tumor
0
Cell Cycle Proteins
0
MTSS1 protein, human
0
Microfilament Proteins
0
Mtss1 protein, mouse
0
Neoplasm Proteins
0
Cytarabine
04079A1RDZ
Protein-Tyrosine Kinases
EC 2.7.10.1
WEE1 protein, human
EC 2.7.10.2
Daunorubicin
ZS7284E0ZP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2827-2839Subventions
Organisme : European Research Council
ID : 636855
Pays : International
Organisme : Austrian Science Fund FWF
ID : P 28256
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : P 28013
Pays : Austria
Informations de copyright
© 2021. The Author(s).
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