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223 results on '"Jun, Qi"'

15. BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma

Author

Keiji Kurata, Mehmet K. Samur, Priscilla Liow, Kenneth Wen, Leona Yamamoto, Jiye Liu, Eugenio Morelli, Annamaria Gulla, Yu-Tzu Tai, Jun Qi, Teru Hideshima, and Kenneth C. Anderson

Subjects
Cancer Research, Oncology
Abstract

Purpose: BRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple myeloma, its clinical significance and oncogenic mechanism have not yet been elucidated. Here, we sought to identify the clinical and biological impact of BRD9 in multiple myeloma, which may contribute to the development of novel therapeutic strategies. Experimental Design: We performed integrated analyses of BRD9 in vitro and in vivo using multiple myeloma cell lines and primary multiple myeloma cells in established preclinical models, which identified the molecular functions of BRD9 contributing to multiple myeloma cell survival. Results: We found that high BRD9 expression was a poor prognostic factor in multiple myeloma. Depleting BRD9 by genetic (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting chimera; BRD9 degrader) approaches downregulated ribosome biogenesis genes, decreased the expression of the master regulator MYC, and disrupted the protein-synthesis maintenance machinery, thereby inhibiting multiple myeloma cell growth in vitro and in vivo in preclinical models. Importantly, we identified that the expression of ribosome biogenesis genes was associated with the disease progression and prognosis of patients with multiple myeloma. Our results suggest that BRD9 promotes gene expression by predominantly occupying the promoter regions of ribosome biogenesis genes and cooperating with BRD4 to enhance the transcriptional function of MYC. Conclusions: Our study identifies and validates BRD9 as a novel therapeutic target in preclinical models of multiple myeloma, which provides the framework for the clinical evaluation of BRD9 degraders to improve patient outcome.

Published
2023

16. BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Author

Eshini Panditharatna, Joana G. Marques, Tingjian Wang, Maria C. Trissal, Ilon Liu, Li Jiang, Alexander Beck, Andrew Groves, Neekesh V. Dharia, Deyao Li, Samantha E. Hoffman, Guillaume Kugener, McKenzie L. Shaw, Hafsa M. Mire, Olivia A. Hack, Joshua M. Dempster, Caleb Lareau, Lingling Dai, Logan H. Sigua, Michael A. Quezada, Ann-Catherine J. Stanton, Meghan Wyatt, Zohra Kalani, Amy Goodale, Francisca Vazquez, Federica Piccioni, John G. Doench, David E. Root, Jamie N. Anastas, Kristen L. Jones, Amy Saur Conway, Sylwia Stopka, Michael S. Regan, Yu Liang, Hyuk-Soo Seo, Kijun Song, Puspalata Bashyal, William P. Jerome, Nathan D. Mathewson, Sirano Dhe-Paganon, Mario L. Suvà, Angel M. Carcaboso, Cinzia Lavarino, Jaume Mora, Quang-De Nguyen, Keith L. Ligon, Yang Shi, Sameer Agnihotri, Nathalie Y.R. Agar, Kimberly Stegmaier, Charles D. Stiles, Michelle Monje, Todd R. Golub, Jun Qi, and Mariella G. Filbin

Subjects
Mammals, Epigenome, Oncology, Mutation, Neoplastic Stem Cells, DNA Helicases, Animals, Humans, Nuclear Proteins, Glioma, Transcription Factors
Abstract

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.

Published
2022

19. Data from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma

Author

Kenneth C. Anderson, Teru Hideshima, Jun Qi, Yu-Tzu Tai, Annamaria Gulla, Eugenio Morelli, Jiye Liu, Leona Yamamoto, Kenneth Wen, Priscilla Liow, Mehmet K. Samur, and Keiji Kurata

Abstract

Purpose:BRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple myeloma, its clinical significance and oncogenic mechanism have not yet been elucidated. Here, we sought to identify the clinical and biological impact of BRD9 in multiple myeloma, which may contribute to the development of novel therapeutic strategies.Experimental Design:We performed integrated analyses of BRD9 in vitro and in vivo using multiple myeloma cell lines and primary multiple myeloma cells in established preclinical models, which identified the molecular functions of BRD9 contributing to multiple myeloma cell survival.Results:We found that high BRD9 expression was a poor prognostic factor in multiple myeloma. Depleting BRD9 by genetic (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting chimera; BRD9 degrader) approaches downregulated ribosome biogenesis genes, decreased the expression of the master regulator MYC, and disrupted the protein-synthesis maintenance machinery, thereby inhibiting multiple myeloma cell growth in vitro and in vivo in preclinical models. Importantly, we identified that the expression of ribosome biogenesis genes was associated with the disease progression and prognosis of patients with multiple myeloma. Our results suggest that BRD9 promotes gene expression by predominantly occupying the promoter regions of ribosome biogenesis genes and cooperating with BRD4 to enhance the transcriptional function of MYC.Conclusions:Our study identifies and validates BRD9 as a novel therapeutic target in preclinical models of multiple myeloma, which provides the framework for the clinical evaluation of BRD9 degraders to improve patient outcome.

Published
2023

21. Supplementary Figure S2 from Lysine Demethylase 5A Is Required for MYC-Driven Transcription in Multiple Myeloma

Author

Jun Qi, Teru Hideshima, Kenneth C. Anderson, Adam D. Durbin, Udo Oppermann, Javed Khan, Shannon Lauberth, Takashi Minami, Mitsuyoshi Nakao, Sumio Ohtsuki, Masao Matsuoka, Nikhil C. Munshi, Yu-Tzu Tai, Mehmet K. Samur, Yawara Kawano, Shingo Usuki, Shinjiro Hino, Yong Kim, Virangika K. Wimalasena, Catrine Johansson, Takeshi Masuda, Chengkui Pei, Deyao Li, Xiaofeng Zhang, Keiji Kurata, Daisuke Ogiya, Berkley E. Gryder, Tingjian Wang, Paul M.C. Park, and Hiroto Ohguchi

Abstract

Supplementary Figure S2 shows the selectivity of JQKD82 against KDM5 in biochemical assay and in MM cells

Published
2023

22. Data from Lysine Demethylase 5A Is Required for MYC-Driven Transcription in Multiple Myeloma

Author

Jun Qi, Teru Hideshima, Kenneth C. Anderson, Adam D. Durbin, Udo Oppermann, Javed Khan, Shannon Lauberth, Takashi Minami, Mitsuyoshi Nakao, Sumio Ohtsuki, Masao Matsuoka, Nikhil C. Munshi, Yu-Tzu Tai, Mehmet K. Samur, Yawara Kawano, Shingo Usuki, Shinjiro Hino, Yong Kim, Virangika K. Wimalasena, Catrine Johansson, Takeshi Masuda, Chengkui Pei, Deyao Li, Xiaofeng Zhang, Keiji Kurata, Daisuke Ogiya, Berkley E. Gryder, Tingjian Wang, Paul M.C. Park, and Hiroto Ohguchi

Abstract

Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3 lysine 4 trimethy­lation (H3K4me3), a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC-targeted genes in multiple myeloma cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself by supporting TFIIH (CDK7)- and P-TEFb (CDK9)–mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in multiple myeloma functioning through regulation of MYC target gene transcription and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for multiple myeloma.Significance:We delineate the function of KDM5A in activating the MYC-driven transcriptional landscape. We develop a cell-permeable KDM5 inhibitor to define the activating role of KDM5A on MYC target gene expression and implicate the therapeutic potential of this compound in mouse models and multiple myeloma patient samples.See related video from the AACR Annual Meeting 2021: https://vimeo.com/554896826

Published
2023

23. Supplementary Table S2 from Lysine Demethylase 5A Is Required for MYC-Driven Transcription in Multiple Myeloma

Author

Jun Qi, Teru Hideshima, Kenneth C. Anderson, Adam D. Durbin, Udo Oppermann, Javed Khan, Shannon Lauberth, Takashi Minami, Mitsuyoshi Nakao, Sumio Ohtsuki, Masao Matsuoka, Nikhil C. Munshi, Yu-Tzu Tai, Mehmet K. Samur, Yawara Kawano, Shingo Usuki, Shinjiro Hino, Yong Kim, Virangika K. Wimalasena, Catrine Johansson, Takeshi Masuda, Chengkui Pei, Deyao Li, Xiaofeng Zhang, Keiji Kurata, Daisuke Ogiya, Berkley E. Gryder, Tingjian Wang, Paul M.C. Park, and Hiroto Ohguchi

Abstract

Supplementary Table S2 shows the ChIP-seq data with the peaks significantly overlap with KDM5A ChIP-seq peaks MM1S

Published
2023

24. Supplementary Data from EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

Author

Jun Qi, A. Thomas Look, Kimberly Stegmaier, Brian J. Abraham, Martha L. Bulyk, Ernst Schönbrunn, John Easton, Olaf Wiest, Taylor R. Quinn, Melissa J. Bikowitz, Antonio R. Perez-Atayde, Amanda L. Robichaud, Amy Saur Conway, Ken Morita, Logan H. Sigua, Paul M.C. Park, Lily Maxham, Maya Mundada, Ying Shao, Anand G. Patel, Stephanie Nance, Noha A.M. Shendy, Luca Mariani, Neekesh V. Dharia, Deyao Li, Mark W. Zimmerman, Virangika K. Wimalasena, Tingjian Wang, and Adam D. Durbin

Abstract

Supplementary Data from EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

Published
2023

25. Supplementary Table from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Author

Mariella G. Filbin, Jun Qi, Todd R. Golub, Michelle Monje, Charles D. Stiles, Kimberly Stegmaier, Nathalie Y.R. Agar, Sameer Agnihotri, Yang Shi, Keith L. Ligon, Quang-De Nguyen, Jaume Mora, Cinzia Lavarino, Angel M. Carcaboso, Mario L. Suvà, Sirano Dhe-Paganon, Nathan D. Mathewson, William P. Jerome, Puspalata Bashyal, Kijun Song, Hyuk-Soo Seo, Yu Liang, Michael S. Regan, Sylwia Stopka, Amy Saur Conway, Kristen L. Jones, Jamie N. Anastas, David E. Root, John G. Doench, Federica Piccioni, Francisca Vazquez, Amy Goodale, Zohra Kalani, Meghan Wyatt, Ann-Catherine J. Stanton, Michael A. Quezada, Logan H. Sigua, Lingling Dai, Caleb Lareau, Joshua M. Dempster, Olivia A. Hack, Hafsa M. Mire, McKenzie L. Shaw, Guillaume Kugener, Samantha E. Hoffman, Deyao Li, Neekesh V. Dharia, Andrew Groves, Alexander Beck, Li Jiang, Ilon Liu, Maria C. Trissal, Tingjian Wang, Joana G. Marques, and Eshini Panditharatna

Abstract

Supplementary Table from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Published
2023

26. Supplementary Figure from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Author

Mariella G. Filbin, Jun Qi, Todd R. Golub, Michelle Monje, Charles D. Stiles, Kimberly Stegmaier, Nathalie Y.R. Agar, Sameer Agnihotri, Yang Shi, Keith L. Ligon, Quang-De Nguyen, Jaume Mora, Cinzia Lavarino, Angel M. Carcaboso, Mario L. Suvà, Sirano Dhe-Paganon, Nathan D. Mathewson, William P. Jerome, Puspalata Bashyal, Kijun Song, Hyuk-Soo Seo, Yu Liang, Michael S. Regan, Sylwia Stopka, Amy Saur Conway, Kristen L. Jones, Jamie N. Anastas, David E. Root, John G. Doench, Federica Piccioni, Francisca Vazquez, Amy Goodale, Zohra Kalani, Meghan Wyatt, Ann-Catherine J. Stanton, Michael A. Quezada, Logan H. Sigua, Lingling Dai, Caleb Lareau, Joshua M. Dempster, Olivia A. Hack, Hafsa M. Mire, McKenzie L. Shaw, Guillaume Kugener, Samantha E. Hoffman, Deyao Li, Neekesh V. Dharia, Andrew Groves, Alexander Beck, Li Jiang, Ilon Liu, Maria C. Trissal, Tingjian Wang, Joana G. Marques, and Eshini Panditharatna

Abstract

Supplementary Figure from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Published
2023

27. Supplementary Method from Lysine Demethylase 5A Is Required for MYC-Driven Transcription in Multiple Myeloma

Author

Jun Qi, Teru Hideshima, Kenneth C. Anderson, Adam D. Durbin, Udo Oppermann, Javed Khan, Shannon Lauberth, Takashi Minami, Mitsuyoshi Nakao, Sumio Ohtsuki, Masao Matsuoka, Nikhil C. Munshi, Yu-Tzu Tai, Mehmet K. Samur, Yawara Kawano, Shingo Usuki, Shinjiro Hino, Yong Kim, Virangika K. Wimalasena, Catrine Johansson, Takeshi Masuda, Chengkui Pei, Deyao Li, Xiaofeng Zhang, Keiji Kurata, Daisuke Ogiya, Berkley E. Gryder, Tingjian Wang, Paul M.C. Park, and Hiroto Ohguchi

Abstract

Supplementary Methods, compound synthesis, Supplementary Materials and Supplementary References

Published
2023

28. Data from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Author

Mariella G. Filbin, Jun Qi, Todd R. Golub, Michelle Monje, Charles D. Stiles, Kimberly Stegmaier, Nathalie Y.R. Agar, Sameer Agnihotri, Yang Shi, Keith L. Ligon, Quang-De Nguyen, Jaume Mora, Cinzia Lavarino, Angel M. Carcaboso, Mario L. Suvà, Sirano Dhe-Paganon, Nathan D. Mathewson, William P. Jerome, Puspalata Bashyal, Kijun Song, Hyuk-Soo Seo, Yu Liang, Michael S. Regan, Sylwia Stopka, Amy Saur Conway, Kristen L. Jones, Jamie N. Anastas, David E. Root, John G. Doench, Federica Piccioni, Francisca Vazquez, Amy Goodale, Zohra Kalani, Meghan Wyatt, Ann-Catherine J. Stanton, Michael A. Quezada, Logan H. Sigua, Lingling Dai, Caleb Lareau, Joshua M. Dempster, Olivia A. Hack, Hafsa M. Mire, McKenzie L. Shaw, Guillaume Kugener, Samantha E. Hoffman, Deyao Li, Neekesh V. Dharia, Andrew Groves, Alexander Beck, Li Jiang, Ilon Liu, Maria C. Trissal, Tingjian Wang, Joana G. Marques, and Eshini Panditharatna

Abstract

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas.Significance:Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.See related commentary by Beytagh and Weiss, p. 2730.See related article by Mo et al., p. 2906.This article is highlighted in the In This Issue feature, p. 2711

Published
2023

29. Data from EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

Author

Jun Qi, A. Thomas Look, Kimberly Stegmaier, Brian J. Abraham, Martha L. Bulyk, Ernst Schönbrunn, John Easton, Olaf Wiest, Taylor R. Quinn, Melissa J. Bikowitz, Antonio R. Perez-Atayde, Amanda L. Robichaud, Amy Saur Conway, Ken Morita, Logan H. Sigua, Paul M.C. Park, Lily Maxham, Maya Mundada, Ying Shao, Anand G. Patel, Stephanie Nance, Noha A.M. Shendy, Luca Mariani, Neekesh V. Dharia, Deyao Li, Mark W. Zimmerman, Virangika K. Wimalasena, Tingjian Wang, and Adam D. Durbin

Abstract

Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells.Significance:EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner.This article is highlighted in the In This Issue feature, p. 587

Published
2023

30. Figure S15 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

Primary clustering of tumor cells and immune cell populations

Published
2023

31. Table S2 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

Author

Kwok-Kin Wong, George Miller, Jun Qi, Gordon J. Freeman, Vamsidhar Velcheti, Peter S. Hammerman, Thales Papagiannakopoulos, Aristotelis Tsirigos, Kandarp Jani, Alexandra R. Rabin, Heather Silver, Kristen Labbe, Christina Almonte, Ece Bagdatlioglu, Catríona M. Dowling, Val Pyon, Zhaoyuan Fang, Michela Ranieri, Jiehui Deng, Ting Chen, Wei Wang, Alireza Khodadadi-Jamayran, Wai-Lung Ng, Hua Zhang, Hai Hu, Troy A. Luster, Qingyuan Huang, and Fei Li

Abstract

MAGeCK analysis of CRISPR screen

Published
2023

32. Figure S9 from The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies

Author

Alexandre Puissant, Raphael Itzykson, Kris C. Wood, Camille Lobry, Kimberly Stegmaier, Hava M. Golan, Lina Benajiba, Nina Fenouille, Claude Preudhomme, Hervé Dombret, Thomas Cluzeau, Giovanni Roti, Jean-Baptiste Micol, Marie-Hélène Schlageter, Jun Qi, Yana Pikman, Alain Pruvost, Jean-François Benoist, Gabriela Alexe, Iléana Antony-Debré, Justine Pasanisi, Gael Fortin, Christopher F. Bassil, Justine C. Rutter, Kevin H. Lin, Bryann Pardieu, Antoine Forget, Reinaldo Dal Bello, Chaïma Benaksas, Gaetano Sodaro, Camille Vaganay, Frank Ling, and Angela Su

Abstract

Effect of MTHFR impairment on response to OTX015.

Published
2023

35. Table S6 from The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies

Author

Alexandre Puissant, Raphael Itzykson, Kris C. Wood, Camille Lobry, Kimberly Stegmaier, Hava M. Golan, Lina Benajiba, Nina Fenouille, Claude Preudhomme, Hervé Dombret, Thomas Cluzeau, Giovanni Roti, Jean-Baptiste Micol, Marie-Hélène Schlageter, Jun Qi, Yana Pikman, Alain Pruvost, Jean-François Benoist, Gabriela Alexe, Iléana Antony-Debré, Justine Pasanisi, Gael Fortin, Christopher F. Bassil, Justine C. Rutter, Kevin H. Lin, Bryann Pardieu, Antoine Forget, Reinaldo Dal Bello, Chaïma Benaksas, Gaetano Sodaro, Camille Vaganay, Frank Ling, and Angela Su

Abstract

List of sgRNA Guides Used in the CRISPR Screen.

Published
2023

36. Supplementary Table 3 from Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer

Author

Kwok-Kin Wong, James E. Bradner, Henry Long, Karen Cichowski, Myles Brown, Peter S. Hammerman, Carla F. Kim, Christine Fillmore Brainson, Hideo Watanabe, Roderick T. Bronson, Joshiawa Paulk, Jacob B. Reibel, Charles M. Perou, Julian Carretero, Eiki Kikuchi, Grit S. Herter-Sprie, Yanxi Zhang, Melissa A. Duarte, Yan Liu, Yvonne Y. Li, Thomas De Raedt, Alexander Federation, Matthew A. Lawlor, Jennifer A. Perry, Charles Y. Lin, Fugen Li, Prakash K. Rao, Lewyn Li, Jaime M. Reyes, Jun Qi, and Haikuo Zhang

Abstract

Supplementary Table 3. Quality Control of RNA-Sequencing Data.

Published
2023

37. Supplementary Figures S1 - S5, Tables S1 - S2 from Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer

Author

Kwok-Kin Wong, James E. Bradner, Henry Long, Karen Cichowski, Myles Brown, Peter S. Hammerman, Carla F. Kim, Christine Fillmore Brainson, Hideo Watanabe, Roderick T. Bronson, Joshiawa Paulk, Jacob B. Reibel, Charles M. Perou, Julian Carretero, Eiki Kikuchi, Grit S. Herter-Sprie, Yanxi Zhang, Melissa A. Duarte, Yan Liu, Yvonne Y. Li, Thomas De Raedt, Alexander Federation, Matthew A. Lawlor, Jennifer A. Perry, Charles Y. Lin, Fugen Li, Prakash K. Rao, Lewyn Li, Jaime M. Reyes, Jun Qi, and Haikuo Zhang

Abstract

Supplementary Figure S1. Generation of LSL-EZH2 conditional transgenic mice. Supplementary Figure S2. H3K27ac super enhancer analysis in EZH2 mouse lung tumors. Supplementary Figure S3. Human NSCLC cells with low levels of EZH2 are not sensitive to disruption of EZH2. Supplementary Figure S4. Development and characterization of JQEZ5. Supplementary Figure S5. Cellular and in vivo characterization of JQEZ5. Supplementary Table S1. Summary of LSL-EZH2 mouse models. Supplementary Table S2. Summary of lung adenocarcinoma in LSL-EZH2 mouse models.

Published
2023

41. Supplementary Table 1 from Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma

Author

Michael A. Caligiuri, Pierluigi Porcu, James E. Bradner, Guido Marcucci, Jianying Zhang, Giandomenico Russo, Henry Wong, Jun Qi, Kathleen McConnell, Jing Wen, Douglas P. Curphey, Jessica Johns, Gregory H. Sams, Laura A. Sullivan, Sonya Kwiatkowski, Krista La Perle, and Anjali Mishra

Abstract

Supplementary Table 1A (ST1A). Clinical features of CTCL (MF and SS) patients used in Figure 1B and Figure 4E (denoted with *). Stage 1B and IIB are MF samples and Stage III/IV are SS samples. Supplementary Table 1B (ST1B). Clinical features of SS patients whose CD4+ T cells were used in Figure 1C. Supplementary Table 1C (ST1C). Clinical features of SS patients whose CD4+ T cells were used in Figure 5B and Supplementary Figure 1D-F (denoted with #). Supplementary Table 1D (ST1D). Clinical features of SS patients whose CD4+ T cells were used in Figure 4D and 5A.

Published
2023

45. Supplementary Tables 1 - 9 from Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition

Author

Kimberly Stegmaier, James E. Bradner, William A. Weiss, Andrew L. Kung, Cyril H. Benes, Ultan McDermott, Matthew J. Garnett, Patricia Greninger, William Clay Gustafson, Rhamy Zeid, Erin A. Nekritz, Yvan H. Chanthery, Jun Qi, Christopher F. Bassil, Gabriela Alexe, Stacey M. Frumm, and Alexandre Puissant

Abstract

PDF file - 93K, This file contains 9 supplementary tables including the full primary screening data and secondary testing of BETi in neuroblastoma, supporting tables for the expression profiling analyses, and the list of Affymetrix probes (MYCN) and shRNA sequences for BRD4 and MYCN.

Published
2023

49. Data from Targeting STAT5 in Hematologic Malignancies through Inhibition of the Bromodomain and Extra-Terminal (BET) Bromodomain Protein BRD2

Author

David A. Frank, James E. Bradner, Martha Wadleigh, Richard M. Stone, Jun Qi, Patricia A. Toniolo, Michael Xiang, Robert Cerulli, Erik A. Nelson, Sarah R. Walker, and Suhu Liu

Abstract

The transcription factor signal STAT5 is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematologic malignancies. Given the importance of bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacologic bromodomain inhibitor could inhibit STAT5-dependent gene expression. We found that the small-molecule bromodomain and extra-terminal (BET) bromodomain inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET bromodomain subfamily of proteins, it seems that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T-cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knockdown or JQ1 treatment shows strong synergy with tyrosine kinase inhibitors (TKI) in inducing apoptosis in leukemia cells. In contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and TKIs may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation. Mol Cancer Ther; 13(5); 1194–205. ©2014 AACR.

Published
2023

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