Control of focal adhesion kinase activation by RUNX1-regulated miRNAs in high-risk AML.

Autor: Akhade VS; Department of Pathology & Laboratory Medicine, University of British Columbia, G105 - 2211 Wesbrook Mall, BC V6T 2B5, Vancouver, BC, Canada.; Canada's Michael Smith Genome Sciences Centre, BC Cancer, 675 W10 Ave, BC V5Z 1L3, Vancouver, BC, Canada., Liu T; Canada's Michael Smith Genome Sciences Centre, BC Cancer, 675 W10 Ave, BC V5Z 1L3, Vancouver, BC, Canada., Docking TR; Canada's Michael Smith Genome Sciences Centre, BC Cancer, 675 W10 Ave, BC V5Z 1L3, Vancouver, BC, Canada., Jiang J; Canada's Michael Smith Genome Sciences Centre, BC Cancer, 675 W10 Ave, BC V5Z 1L3, Vancouver, BC, Canada., Gopal A; Canada's Michael Smith Genome Sciences Centre, BC Cancer, 675 W10 Ave, BC V5Z 1L3, Vancouver, BC, Canada., Karsan A; Department of Pathology & Laboratory Medicine, University of British Columbia, G105 - 2211 Wesbrook Mall, BC V6T 2B5, Vancouver, BC, Canada. akarsan@bcgsc.ca.; Canada's Michael Smith Genome Sciences Centre, BC Cancer, 675 W10 Ave, BC V5Z 1L3, Vancouver, BC, Canada. akarsan@bcgsc.ca.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2023 Apr; Vol. 37 (4), pp. 776-787. Date of Electronic Publication: 2023 Feb 14.
DOI: 10.1038/s41375-023-01841-z
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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