Anti-Leukemic Effects of Velcrin in SLFN12-Expressing Acute Myeloid Leukemia
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PROVIDER: PRJNA1258184 | ENA |
REPOSITORIES: ENA
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Project description:Schlafen 12 (SLFN12) is a member of the Schlafen (SLFN) family of proteins, a group of interferon-stimulated genes with diverse roles in cellular regulation with implications for human malignancies. Accumulating evidence indicates that SLFN family proteins may serve as prognostic markers across various cancer types. In acute myeloid leukemia (AML), SLFN12 is notably overexpressed, which prompted us to investigate its potential as a therapeutic target. Employing a panel of leukemia cell lines, we explored the effects of velcrins, a class of small molecules able to modulate SLFN12 biological activity. Mechanistic studies showed that velcrin treatment increases expression of SLFN12 and promotes SLFN12 complex formation with PDE3A or PDE3B. Functionally, these effects were associated with growth inhibition and induction of apoptosis. Further, velcrin treatment induced potent suppressive effects on the clonogenic capability of primary human AML progenitors and suppressed tumor growth and significantly extended survival in a mouse AML xenograft model. Taken together, these findings highlight the potential of using velcrins as a promising therapeutic strategy for the treatment of AML patients.
2025-09-04 | GSE296195 | GEO
Project description:Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
2022-09-01 | GSE185827 | GEO
Project description:Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
2022-09-01 | GSE185826 | GEO
Project description:Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
2022-09-01 | GSE185822 | GEO
Project description:Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death
| PRJNA770951 | ENA
Project description:Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death [tRNA seq]
| PRJNA770961 | ENA
Project description:Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death [Ribo-Seq]
| PRJNA770962 | ENA
Project description:Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death [RNA-Seq]
| PRJNA770957 | ENA
Project description:Garvie CW, Wu X, Papanastasiou M, Lee S, Fuller J, Schnitzler GR, Horner SW, Baker A, Zhang T, Mullahoo JP, Westlake L, Hoyt SH, Toetzl M, Ranaghan M, de Waal L, McGaunn J, Kaplan B, Piccioni F, Yang X, Lange M, Tersteegen A, Raymond D, Lewis TA, Carr SA, Cherniack AD, Lemke C, Meyerson M, Greulich H. 2021. DNMDP and related compounds, or "velcrins", induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.
2021-06-14 | MSV000087620 | MassIVE
Project description:In this study, we use pre-malignant cells from different Cebpa mutant acute myeloid leukemia (AML) models. We have used conditional KO models (CreLoxP) and isolated hematopoietic cells shortly after induction of recombination, in order to look at pre-leukemic cells, which have acquired the first hit, but not yet undergone full malignant transformation. We have sorted granulocyte-macrophage progenitors (GMPs) and the more immature population pre-granulocyte-macrophages (preGMs) from pre-leukemic mice. We analyzed gene-expression profiles in order to find deregulated genes, which make the cells more prone to undergo transformation.
2013-07-08 | E-GEOD-47813 | biostudies-arrayexpress