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12 results on '"Andrew W. Stamford"'

1. Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

Author

Yiman Liu, Qinglan Li, Fatemeh Alikarami, Declan R. Barrett, Leila Mahdavi, Hangpeng Li, Sylvia Tang, Tanweer A. Khan, Mayako Michino, Connor Hill, Lele Song, Lu Yang, Yuanyuan Li, Sheela Pangeni Pokharel, Andrew W. Stamford, Nigel Liverton, Louis M. Renzetti, Simon Taylor, Gillian F. Watt, Tammy Ladduwahetty, Stacia Kargman, Peter T. Meinke, Michael A. Foley, Junwei Shi, Haitao Li, Martin Carroll, Chun-Wei Chen, Alessandro Gardini, Ivan Maillard, David J. Huggins, Kathrin M. Bernt, and Liling Wan

Subjects
Histones, Leukemia, Myeloid, Acute, Oncology, Lysine, Humans, Chromatin, Myeloid-Lymphoid Leukemia Protein
Abstract

The chromatin reader eleven–nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9–mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line– and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach. Significance: AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483

Published
2022

2. Supplementary Data from Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

Author

Liling Wan, Kathrin M. Bernt, David J. Huggins, Ivan Maillard, Alessandro Gardini, Chun-Wei Chen, Martin Carroll, Haitao Li, Junwei Shi, Michael A. Foley, Peter T. Meinke, Stacia Kargman, Tammy Ladduwahetty, Gillian F. Watt, Simon Taylor, Louis M. Renzetti, Nigel Liverton, Andrew W. Stamford, Sheela Pangeni Pokharel, Yuanyuan Li, Lu Yang, Lele Song, Connor Hill, Mayako Michino, Tanweer A. Khan, Sylvia Tang, Hangpeng Li, Leila Mahdavi, Declan R. Barrett, Fatemeh Alikarami, Qinglan Li, and Yiman Liu

Abstract

Supplementary Data from Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

Published
2023

3. Data from Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

Author

Liling Wan, Kathrin M. Bernt, David J. Huggins, Ivan Maillard, Alessandro Gardini, Chun-Wei Chen, Martin Carroll, Haitao Li, Junwei Shi, Michael A. Foley, Peter T. Meinke, Stacia Kargman, Tammy Ladduwahetty, Gillian F. Watt, Simon Taylor, Louis M. Renzetti, Nigel Liverton, Andrew W. Stamford, Sheela Pangeni Pokharel, Yuanyuan Li, Lu Yang, Lele Song, Connor Hill, Mayako Michino, Tanweer A. Khan, Sylvia Tang, Hangpeng Li, Leila Mahdavi, Declan R. Barrett, Fatemeh Alikarami, Qinglan Li, and Yiman Liu

Abstract

The chromatin reader eleven–nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9–mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line– and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach.Significance:AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation.This article is highlighted in the In This Issue feature, p. 2483

Published
2023

4. Supplementary Table 2 from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Supplementary Table 2

Published
2023

5. Supplementary figure S4 from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Supplementary figure S4

Published
2023

6. Data from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Pancreatic adenocarcinoma (PDAC) epitomizes a deadly cancer driven by abnormal KRAS signaling. Here, we show that the eIF4A RNA helicase is required for translation of key KRAS signaling molecules and that pharmacological inhibition of eIF4A has single-agent activity against murine and human PDAC models at safe dose levels. EIF4A was uniquely required for the translation of mRNAs with long and highly structured 5′ untranslated regions, including those with multiple G-quadruplex elements. Computational analyses identified these features in mRNAs encoding KRAS and key downstream molecules. Transcriptome-scale ribosome footprinting accurately identified eIF4A-dependent mRNAs in PDAC, including critical KRAS signaling molecules such as PI3K, RALA, RAC2, MET, MYC, and YAP1. These findings contrast with a recent study that relied on an older method, polysome fractionation, and implicated redox-related genes as eIF4A clients. Together, our findings highlight the power of ribosome footprinting in conjunction with deep RNA sequencing in accurately decoding translational control mechanisms and define the therapeutic mechanism of eIF4A inhibitors in PDAC.Significance:These findings document the coordinate, eIF4A-dependent translation of RAS-related oncogenic signaling molecules and demonstrate therapeutic efficacy of eIF4A blockade in pancreatic adenocarcinoma.

Published
2023

7. Supplementary Figure S1 from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Supplementary Figure S1

Published
2023

8. Supplementary Table 4 from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Supplementary Table 4

Published
2023

9. Supplementary Figure S5 from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Supplementary Figure S5

Published
2023

10. Supplementary Table 1 from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Supplementary Table 1

Published
2023

11. Supplementary Table 3 from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Supplementary Table 3

Published
2023

12. Supplementary Figure S2 from Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules

Author

Hans-Guido Wendel, Zhengqing Ouyang, Steven D. Leach, Gunnar Rätsch, Peter T. Meinke, Andrew W. Stamford, Elisa de Stanchina, Agnes Viale, Ouathek Ouerfelli, Guangli Yang, Yoshiyuki Fukase, Mark Duggan, Rachel K. Beyer, Jerry P. Melchor, Qing Chang, Paul B. Romesser, Stefan G. Stark, Antonija Burčul, Olivera Grbovic-Huezo, Man Jiang, Viraj R. Sanghvi, Askan Gokce, Prathibha Mohan, Nicolas Lecomte, Jianan Lin, and Kamini Singh

Abstract

Supplementary Figure S2

Published
2023

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