Control of focal adhesion kinase activation by RUNX1-regulated miRNAs in high-risk AML.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
28
06
2022
accepted:
03
02
2023
revised:
29
01
2023
medline:
10
4
2023
pubmed:
15
2
2023
entrez:
14
2
2023
Statut:
ppublish
Résumé
We recently described a 16-gene expression signature for improved risk stratification of acute myeloid leukemia (AML) patients called the AML Prognostic Score (APS). A subset of APS-high-risk AML patients showed increased levels of focal adhesion kinase (FAK), encoded by the Protein Tyrosine Kinase 2 (PTK2) gene, which was correlated with RUNX1 mutations. RUNX1 mutant cells are more sensitive to PTK2 inhibitors. As we were not able to detect RUNX1-binding sites in the PTK2 promoter, we hypothesized that RUNX1 might regulate micro(mi)RNAs that repress PTK2, such that loss-of-function RUNX1 mutations would result in reduced miRNA expression and derepression of PTK2. Examination of paired RNA-seq and miRNA-seq data from 301 AML cases revealed two miRNAs that positively correlated with RUNX1 expression, contained RUNX1-binding sites in their promoters and were predicted to target PTK2. We show that the hsa-let7a-2-3p and hsa-miR-135a-5p promoters are regulated by RUNX1, and that PTK2 is a direct target of both miRNAs. Even in the absence of RUNX1 mutations, hsa-let7a-2-3p and hsa-miR-135a-5p regulate PTK2 expression, and reduced expression of these two miRNAs sensitizes AML cells to PTK2 inhibition. These data explain how RUNX1 regulates PTK2, and identify potential miRNA biomarkers for targeting AML with PTK2 inhibitors.
Identifiants
pubmed: 36788336
doi: 10.1038/s41375-023-01841-z
pii: 10.1038/s41375-023-01841-z
doi:
Substances chimiques
Core Binding Factor Alpha 2 Subunit
0
Focal Adhesion Kinase 1
EC 2.7.10.2
Focal Adhesion Protein-Tyrosine Kinases
EC 2.7.10.2
MicroRNAs
0
RUNX1 protein, human
0
PTK2 protein, human
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
776-787Subventions
Organisme : CIHR
ID : PJT-166051
Pays : Canada
Organisme : CIHR
ID : PJT-162131
Pays : Canada
Organisme : CIHR
ID : PJT-183924
Pays : Canada
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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