Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug;39(8):2021-2025.
doi: 10.1038/s41375-025-02661-z. Epub 2025 Jun 26.

DCPS is a synthetic lethal therapeutic target in acute myeloid leukemia expressing low levels of FHIT

Francesca Grassi  1   2 , Madhurendra Singh  1 , Simon Moussaud  1 , Gabriela Vazquez Rodriguez  3 , Zaheer Ali  3 , Kirsten Janssen  1 , Mathilde Cheray  1 , Elory Leonard  2 , Martin Andersson  1 , Angelo de Milito  1 , Hong Qian  2 , Julian Walfridsson  2   4 , Andreas Höglund  5
Affiliations

DCPS is a synthetic lethal therapeutic target in acute myeloid leukemia expressing low levels of FHIT

Francesca Grassi et al. Leukemia. 2025 Aug.
No abstract available

PubMed Disclaimer

Conflict of interest statement

Competing interests: AH, FG, MS, SM, MC, MA, and ADM, are employees of Sprint Bioscience AB. AH, MA, and ADM, are shareholders in Sprint Bioscience AB. JW, is the founder of NeoTargets AB. GVR and ZA are employees of BioReperia AB. EL, and HQ, declare no conflict of interest.

Figures

Fig. 1
Fig. 1. FHIT expression along with mutations in DNMT3A and FLT3 modulates the response of AML to DCPS inhibition.
A Scatterplot showing the Pearson correlations between DCPS dependency score (Chronos Gene Effect) and FHIT expression (log2(TPM + 1)) in AML cells from DepMap (24Q4); *p = 0.018, R = 0.459. B Immunoblot analyses of DCPS and FHIT expression in AML cell panel. β-actin was used for signal normalization (n = 2). C Scatter plot showing Pearson correlations between IC50 values of AML cell lines treated with RG3039 and relative FHIT protein expression (normalized to β-actin, log-transformed). In green cells with low FHIT expression and sensitive to DCPS inhibition, in red more resistant cells with higher FHIT expression; *p = 0.015, R = 0.680 (n = 3). D Schematic summary of genetic and clinical classification of AML cell panel. FHIT protein expression was quantified in Fig. 1B and Supplementary Fig. 1A. French-American-British (FAB) classification of AML is used. FLT3-ITD is a common AML mutation (~30% cases) and a prognostic indicator of disease outcome. DNMT3A is commonly mutated in AML (~20% cases). E Nonlinear regression curves of viability in AML cells over-expressing FHIT compared to EV. Bar chart shows mean ± SD of IC50 values (n = 4); *p < 0.05, ***p < 0.001, unpaired t test. F Immunoblot analysis of shRNA knock-down of STAT5B in MOLM-13 and OCI-AML3 cells. Bar chart shows mean ± SD of relative viability in STAT5B-KD AML cells compared to EV (n = 3). G Kaplan-Meier survival analysis of AML patients carrying FLT3 and DNMT3A mutations with low (red line) or high (blue line) FHIT expression (z-score relative to log2 RNA Seq RPKM). Log-rank (Mantel-Cox) test was used to determine significant differences, *p = 0.02. H Normalized tumor size of patient-derived AML xenograft models in Zebrafish (ZTX®) treated with doxorubicin and IC90 dose of RG3039 for 72 h, expressed as mean ± SD of percent change compared to vehicle (n = 20); *p < 0.05. **p < 0.01, ***p < 0.001, ****p < 0.001, unpaired t test.
Fig. 2
Fig. 2. DCPS inhibition induces cell cycle arrest and release of differentiation block in AML with low levels of FHIT.
A Flow cytometry analysis of cell cycle upon 24-hour treatment with RG3039 using EdU-Alexa Fluor 647 and PI incorporation. Palbociclib was used as positive control to block S phase. Percentage of EV (red) and FHIT-OE (blue) OCI-AML3 in G1 and S phase is shown on the right as mean ± SD (n = 3). B Immunoblot analyses of G1 R point regulators following treatment with RG3039 for 24 h. Relative expression to DMSO control is normalized to β-actin and shown in C as mean ± SD (n = 3). D Bar chart of luciferase signal induced in THP1-Dual™ wild-type (green) and KO-STING (orange) reporter cells upon treatment with RG3039 for 24 h. Data are shown as mean ± SD of signal normalized to DMSO (n = 3). E Bar chart shows mean ± SD of THP-1 gene expression for ISG15, STAT1, STAT2, IRF7 and IRF9 after 24-hour treatment with RG3039 relative to DMSO (n = 4). Expression was normalized to RPL13A, HPRT1, ACTB, TBP housekeeping genes; *p < 0.05, **p < 0.01, ***p < 0.001, unpaired t test. F Flow cytometry analyses of surface markers for myeloid differentiation in OCI-AML3 EV and FHIT-OE. Data are presented as mean ± SD of Mean Fluorescent Intensity (MFI) or percentage of positive cells (%) (n = 4). G Giemsa May-Grünwald stained representative images of OCI-AML3 treated with RG3039 for 5 days. Macrophages are indicated by red arrows and are only present in EV cell line upon treatment. Scale bar is 20 µm. Quantification is shown on the right as mean ± SD of macrophage ratio compared to DMSO (n = 3). H Relative number of colonies to DMSO control formed by EV or FHIT-OE OCI-AML3 treated with RG3039 for 5 days. Data are shown as mean ± SD (n = 3). For all panels significance was calculated using unpaired t test, *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
See this image and copyright information in PMC

References

    1. Yamauchi T, Masuda T, Canver MC, Seiler M, Semba Y, Shboul M, et al. Genome-wide CRISPR-Cas9 screen identifies leukemia-specific dependence on a pre-mRNA metabolic pathway regulated by DCPS. Cancer Cell. 2018;33:386–400. - PMC - PubMed
    1. Wang Z, Kiledjian M. Functional link between the mammalian exosome and mRNA decapping. Cell Press. 2001;107:751–62. - PubMed
    1. Taverniti V, Seraphin B. Elimination of cap structures generated by mRNA decay involves the new scavenger mRNA decapping enzyme Aph1/FHIT together with DcpS. Nucleic Acids Res. 2015;43:482–92. - PMC - PubMed
    1. Gogliotti RG, Cardona H, Singh J, Bail S, Emery C, Kuntz N, et al. The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models. Hum Mol Genet. 2013;22:4084–101. - PMC - PubMed
    1. Skopek R, Palusińska M, Kaczor-Keller K, Pingwara R, Papierniak-Wyglądała A, Schenk T, et al. Choosing the right cell line for acute myeloid leukemia (AML) Research. Int J Mol Sci. 2023;24:5377. - PMC - PubMed

LinkOut - more resources