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1. The ETS transcription factor ETV6 constrains the transcriptional activity of EWS–FLI to promote Ewing sarcoma

Author

Lu, Diana Y., Ellegast, Jana M., Ross, Kenneth N., Malone, Clare F., Lin, Shan, Mabe, Nathaniel W., Dharia, Neekesh V., Meyer, Ashleigh, Conway, Amy, Su, Angela H., Selich-Anderson, Julia, Taslim, Cenny, Byrum, Andrea K., Seong, Bo Kyung A., Adane, Biniam, Gray, Nathanael S., Rivera, Miguel N., Lessnick, Stephen L., and Stegmaier, Kimberly

Published
2023
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2. AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells

Author

Pei, Shanshan, Minhajuddin, Mohammad, Adane, Biniam, Khan, Nabilah, Stevens, Brett M, Mack, Stephen C, Lai, Sisi, Rich, Jeremy N, Inguva, Anagha, Shannon, Kevin M, Kim, Hyunmin, Tan, Aik-Choon, Myers, Jason R, Ashton, John M, Neff, Tobias, Pollyea, Daniel A, Smith, Clayton A, and Jordan, Craig T

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Rare Diseases, Stem Cell Research - Nonembryonic - Human, Stem Cell Research, Hematology, Stem Cell Research - Nonembryonic - Non-Human, Aetiology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, AMP-Activated Protein Kinases, Animals, Cell Self Renewal, Cells, Cultured, Female, Humans, Leukemia, Myeloid, Acute, Membrane Proteins, Mice, Mice, Inbred NOD, Mice, Transgenic, Mitochondrial Proteins, Mitophagy, Neoplastic Stem Cells, Protein Kinase Inhibitors, Signal Transduction, AMPK, FIS1, GSK3, acute myeloid leukemia, differentiation, leukemia stem cells, mitochondrial dynamics, mitophagy, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Because of their unique biology, developing effective methods to eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic overexpression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential. Further, we report that the central metabolic stress regulator AMPK is also intrinsically activated in LSC populations and is upstream of FIS1. Inhibition of AMPK signaling recapitulates the biological effect of FIS1 loss. These data suggest a model in which LSCs co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation.

Published
2018

3. EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes

Author

Huang, Yeying, primary, Durall, R. Taylor, additional, Luong, Nhi M., additional, Hertzler, Hans J., additional, Huang, Julianna, additional, Gokhale, Prafulla C., additional, Leeper, Brittaney A., additional, Persky, Nicole S., additional, Root, David E., additional, Anekal, Praju V., additional, Montero Llopis, Paula D.L.M., additional, David, Clement N., additional, Kutok, Jeffery L., additional, Raimondi, Alejandra, additional, Saluja, Karan, additional, Luo, Jia, additional, Zahnow, Cynthia A., additional, Adane, Biniam, additional, Stegmaier, Kimberly, additional, Hawkins, Catherine E., additional, Ponne, Christopher, additional, Le, Quan, additional, Shapiro, Geoffrey I., additional, Lemieux, Madeleine E., additional, Eagen, Kyle P., additional, and French, Christopher A., additional

Published
2023
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4. EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes

Author

Huang, Yeying, primary, Durall, R Taylor, additional, Luong, Nhi M, additional, Hertzler, Hans J, additional, Huang, Julianna, additional, Gokhale, Prafulla C, additional, Leeper, Brittaney A, additional, Persky, Nicole S, additional, Root, David E, additional, Anekal, Praju V, additional, Montero Llopis, Paula DLM, additional, David, Clement N, additional, Kutok, Jeffery L, additional, Raimondi, Alejandra, additional, Saluja, Karan, additional, Luo, Jia, additional, Zahnow, Cynthia A, additional, Adane, Biniam, additional, Stegmaier, Kimberly, additional, Hawkins, Catherine E, additional, Ponne, Christopher, additional, Le, Quan, additional, Shapiro, Geoffrey I, additional, Lemieux, Madeleine E, additional, Eagen, Kyle P, additional, and French, Christopher A, additional

Published
2023
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5. Supplementary Figures S1-S5 from Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia

Author

Pei, Shanshan, primary, Pollyea, Daniel A., primary, Gustafson, Annika, primary, Stevens, Brett M., primary, Minhajuddin, Mohammad, primary, Fu, Rui, primary, Riemondy, Kent A., primary, Gillen, Austin E., primary, Sheridan, Ryan M., primary, Kim, Jihye, primary, Costello, James C., primary, Amaya, Maria L., primary, Inguva, Anagha, primary, Winters, Amanda, primary, Ye, Haobin, primary, Krug, Anna, primary, Jones, Courtney L., primary, Adane, Biniam, primary, Khan, Nabilah, primary, Ponder, Jessica, primary, Schowinsky, Jeffrey, primary, Abbott, Diana, primary, Hammes, Andrew, primary, Myers, Jason R., primary, Ashton, John M., primary, Nemkov, Travis, primary, D'Alessandro, Angelo, primary, Gutman, Jonathan A., primary, Ramsey, Haley E., primary, Savona, Michael R., primary, Smith, Clayton A., primary, and Jordan, Craig T., primary

Published
2023
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6. Data from An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Author

Lin, Shan, primary, Larrue, Clément, primary, Scheidegger, Nastassja K., primary, Seong, Bo Kyung A., primary, Dharia, Neekesh V., primary, Kuljanin, Miljan, primary, Wechsler, Caroline S., primary, Kugener, Guillaume, primary, Robichaud, Amanda L., primary, Conway, Amy Saur, primary, Mashaka, Thelma, primary, Mouche, Sarah, primary, Adane, Biniam, primary, Ryan, Jeremy A., primary, Mancias, Joseph D., primary, Younger, Scott T., primary, Piccioni, Federica, primary, Lee, Lynn H., primary, Wunderlich, Mark, primary, Letai, Anthony, primary, Tamburini, Jérôme, primary, and Stegmaier, Kimberly, primary

Published
2023
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7. Supplementary Tables from An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Author

Lin, Shan, primary, Larrue, Clément, primary, Scheidegger, Nastassja K., primary, Seong, Bo Kyung A., primary, Dharia, Neekesh V., primary, Kuljanin, Miljan, primary, Wechsler, Caroline S., primary, Kugener, Guillaume, primary, Robichaud, Amanda L., primary, Conway, Amy Saur, primary, Mashaka, Thelma, primary, Mouche, Sarah, primary, Adane, Biniam, primary, Ryan, Jeremy A., primary, Mancias, Joseph D., primary, Younger, Scott T., primary, Piccioni, Federica, primary, Lee, Lynn H., primary, Wunderlich, Mark, primary, Letai, Anthony, primary, Tamburini, Jérôme, primary, and Stegmaier, Kimberly, primary

Published
2023
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8. Supplementary Tables S1-S6 from Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia

Author

Pei, Shanshan, primary, Pollyea, Daniel A., primary, Gustafson, Annika, primary, Stevens, Brett M., primary, Minhajuddin, Mohammad, primary, Fu, Rui, primary, Riemondy, Kent A., primary, Gillen, Austin E., primary, Sheridan, Ryan M., primary, Kim, Jihye, primary, Costello, James C., primary, Amaya, Maria L., primary, Inguva, Anagha, primary, Winters, Amanda, primary, Ye, Haobin, primary, Krug, Anna, primary, Jones, Courtney L., primary, Adane, Biniam, primary, Khan, Nabilah, primary, Ponder, Jessica, primary, Schowinsky, Jeffrey, primary, Abbott, Diana, primary, Hammes, Andrew, primary, Myers, Jason R., primary, Ashton, John M., primary, Nemkov, Travis, primary, D'Alessandro, Angelo, primary, Gutman, Jonathan A., primary, Ramsey, Haley E., primary, Savona, Michael R., primary, Smith, Clayton A., primary, and Jordan, Craig T., primary

Published
2023
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9. Supplementary Data from An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Author

Lin, Shan, primary, Larrue, Clément, primary, Scheidegger, Nastassja K., primary, Seong, Bo Kyung A., primary, Dharia, Neekesh V., primary, Kuljanin, Miljan, primary, Wechsler, Caroline S., primary, Kugener, Guillaume, primary, Robichaud, Amanda L., primary, Conway, Amy Saur, primary, Mashaka, Thelma, primary, Mouche, Sarah, primary, Adane, Biniam, primary, Ryan, Jeremy A., primary, Mancias, Joseph D., primary, Younger, Scott T., primary, Piccioni, Federica, primary, Lee, Lynn H., primary, Wunderlich, Mark, primary, Letai, Anthony, primary, Tamburini, Jérôme, primary, and Stegmaier, Kimberly, primary

Published
2023
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10. Data from Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia

Author

Pei, Shanshan, primary, Pollyea, Daniel A., primary, Gustafson, Annika, primary, Stevens, Brett M., primary, Minhajuddin, Mohammad, primary, Fu, Rui, primary, Riemondy, Kent A., primary, Gillen, Austin E., primary, Sheridan, Ryan M., primary, Kim, Jihye, primary, Costello, James C., primary, Amaya, Maria L., primary, Inguva, Anagha, primary, Winters, Amanda, primary, Ye, Haobin, primary, Krug, Anna, primary, Jones, Courtney L., primary, Adane, Biniam, primary, Khan, Nabilah, primary, Ponder, Jessica, primary, Schowinsky, Jeffrey, primary, Abbott, Diana, primary, Hammes, Andrew, primary, Myers, Jason R., primary, Ashton, John M., primary, Nemkov, Travis, primary, D'Alessandro, Angelo, primary, Gutman, Jonathan A., primary, Ramsey, Haley E., primary, Savona, Michael R., primary, Smith, Clayton A., primary, and Jordan, Craig T., primary

Published
2023
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11. Supplementary Figures from An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Author

Lin, Shan, primary, Larrue, Clément, primary, Scheidegger, Nastassja K., primary, Seong, Bo Kyung A., primary, Dharia, Neekesh V., primary, Kuljanin, Miljan, primary, Wechsler, Caroline S., primary, Kugener, Guillaume, primary, Robichaud, Amanda L., primary, Conway, Amy Saur, primary, Mashaka, Thelma, primary, Mouche, Sarah, primary, Adane, Biniam, primary, Ryan, Jeremy A., primary, Mancias, Joseph D., primary, Younger, Scott T., primary, Piccioni, Federica, primary, Lee, Lynn H., primary, Wunderlich, Mark, primary, Letai, Anthony, primary, Tamburini, Jérôme, primary, and Stegmaier, Kimberly, primary

Published
2023
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14. An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Author

Lin, Shan; https://orcid.org/0000-0002-9699-0250, Larrue, Clément, Scheidegger, Nastassja K; https://orcid.org/0000-0002-3091-2970, Seong, Bo Kyung A; https://orcid.org/0000-0002-1398-6230, Dharia, Neekesh V; https://orcid.org/0000-0001-5048-067X, Kuljanin, Miljan, Wechsler, Caroline S, Kugener, Guillaume; https://orcid.org/0000-0002-4697-2847, Robichaud, Amanda L, Conway, Amy Saur, Mashaka, Thelma, Mouche, Sarah, Adane, Biniam, Ryan, Jeremy A; https://orcid.org/0000-0002-3327-1283, Mancias, Joseph D; https://orcid.org/0000-0002-0692-3717, Younger, Scott T, Piccioni, Federica; https://orcid.org/0000-0003-1210-3210, Lee, Lynn H; https://orcid.org/0000-0002-2898-6196, Wunderlich, Mark; https://orcid.org/0000-0002-2166-5146, Letai, Anthony; https://orcid.org/0000-0002-1993-9013, Tamburini, Jérôme, Stegmaier, Kimberly, Lin, Shan; https://orcid.org/0000-0002-9699-0250, Larrue, Clément, Scheidegger, Nastassja K; https://orcid.org/0000-0002-3091-2970, Seong, Bo Kyung A; https://orcid.org/0000-0002-1398-6230, Dharia, Neekesh V; https://orcid.org/0000-0001-5048-067X, Kuljanin, Miljan, Wechsler, Caroline S, Kugener, Guillaume; https://orcid.org/0000-0002-4697-2847, Robichaud, Amanda L, Conway, Amy Saur, Mashaka, Thelma, Mouche, Sarah, Adane, Biniam, Ryan, Jeremy A; https://orcid.org/0000-0002-3327-1283, Mancias, Joseph D; https://orcid.org/0000-0002-0692-3717, Younger, Scott T, Piccioni, Federica; https://orcid.org/0000-0003-1210-3210, Lee, Lynn H; https://orcid.org/0000-0002-2898-6196, Wunderlich, Mark; https://orcid.org/0000-0002-2166-5146, Letai, Anthony; https://orcid.org/0000-0002-1993-9013, Tamburini, Jérôme, and Stegmaier, Kimberly

Abstract

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. SIGNIFICANCE: There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.This article is highlighted in the In This Issue feature, p. 275.

Published
2022

16. An In Vivo CRISPR Screening Platform to Identify New Therapeutic Targets in AML

Author

Lin, Shan, primary, Larrue, Clement, additional, Scheidegger, Nastassja K., additional, Seong, Bo Kyung A., additional, Dharia, Neekesh V, additional, Wechsler, Caroline, additional, Kugener, Guillaume, additional, Robinchaud, Amanda L, additional, Conway, Amy, additional, Adane, Biniam, additional, Younger, Scott, additional, Piccioni, Federica, additional, Lee, Lynn, additional, Wunderlich, Mark, additional, Tamburini, Jerome, additional, and Stegmaier, Kimberly, additional

Published
2021
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17. Lysosomal Acid Lipase a (LIPA) Modulates Leukemia Stem Cell (LSC) Response to Venetoclax/TKI Combination Therapy in Blast Phase Chronic Myeloid Leukemia

Author

Minhajuddin, Mohd, primary, Ye, Haobin, additional, Winters, Amanda C., additional, Pei, Shanshan, additional, Khan, Nabilah, additional, Stevens, Brett M., additional, Adane, Biniam, additional, Amaya, Maria L., additional, Inguva, Anagha, additional, Krug, Anna, additional, Gasparetto, Maura, additional, Sherbenou, Daniel W., additional, Pollyea, Daniel A., additional, Smith, Clayton, additional, and Jordan, Craig T., additional

Published
2021
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18. SLC5A3 Transports Myo-Inositol to Support the Growth of Acute Myeloid Leukemia

Author

Lin, Shan, primary, Scheidegger, Nastassja K., additional, Alexe, Gabriela, additional, Seong, Bo Kyung A., additional, Dharia, Neekesh V, additional, Wechsler, Caroline, additional, Kugener, Guillaume, additional, Robinchaud, Amanda L, additional, Conway, Amy, additional, Adane, Biniam, additional, Younger, Scott, additional, Piccioni, Federica, additional, Lee, Lynn, additional, Wunderlich, Mark, additional, and Stegmaier, Kimberly, additional

Published
2021
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19. An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Author

Lin, Shan, primary, Larrue, Clément, additional, Scheidegger, Nastassja K., additional, Seong, Bo Kyung A., additional, Dharia, Neekesh V., additional, Kuljanin, Miljan, additional, Wechsler, Caroline S., additional, Kugener, Guillaume, additional, Robichaud, Amanda L., additional, Conway, Amy Saur, additional, Mashaka, Thelma, additional, Mouche, Sarah, additional, Adane, Biniam, additional, Ryan, Jeremy A., additional, Mancias, Joseph D., additional, Younger, Scott T., additional, Piccioni, Federica, additional, Lee, Lynn H., additional, Wunderlich, Mark, additional, Letai, Anthony, additional, Tamburini, Jérôme, additional, and Stegmaier, Kimberly, additional

Published
2021
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20. TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

Author

Seong, Bo Kyung A., primary, Dharia, Neekesh V., additional, Lin, Shan, additional, Donovan, Katherine A., additional, Chong, Shasha, additional, Robichaud, Amanda, additional, Conway, Amy, additional, Hamze, Amanda, additional, Ross, Linda, additional, Alexe, Gabriela, additional, Adane, Biniam, additional, Nabet, Behnam, additional, Ferguson, Fleur M., additional, Stolte, Björn, additional, Wang, Emily Jue, additional, Sun, Jialin, additional, Darzacq, Xavier, additional, Piccioni, Federica, additional, Gray, Nathanael S., additional, Fischer, Eric S., additional, and Stegmaier, Kimberly, additional

Published
2021
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21. STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Author

Adane, Biniam, primary, Alexe, Gabriela, additional, Seong, Bo Kyung A., additional, Lu, Diana, additional, Hwang, Elizabeth E., additional, Hnisz, Denes, additional, Lareau, Caleb A., additional, Ross, Linda, additional, Lin, Shan, additional, Dela Cruz, Filemon S., additional, Richardson, Melissa, additional, Weintraub, Abraham S., additional, Wang, Sarah, additional, Iniguez, Amanda Balboni, additional, Dharia, Neekesh V., additional, Conway, Amy Saur, additional, Robichaud, Amanda L., additional, Tanenbaum, Benjamin, additional, Krill-Burger, John M., additional, Vazquez, Francisca, additional, Schenone, Monica, additional, Berman, Jason N., additional, Kung, Andrew L., additional, Carr, Steven A., additional, Aryee, Martin J., additional, Young, Richard A., additional, Crompton, Brian D., additional, and Stegmaier, Kimberly, additional

Published
2021
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22. STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Author

Adane, Biniam, Alexe, Gabriela, Seong, Bo Kyung A., Lu, Diana, Hwang, Elizabeth E., Hnisz, Denes, Lareau, Caleb A., Ross, Linda, Lin, Shan, Dela Cruz, Filemon S., Richardson, Melissa, Weintraub, Abraham Selby, Wang, Sarah, Iniguez, Amanda Balboni, Dharia, Neekesh V., Conway, Amy Saur, Robichaud, Amanda L., Tanenbaum, Benjamin, Krill-Burger, John M., Vazquez, Francisca, Schenone, Monica, Berman, Jason N., Kung, Andrew L., Carr, Steven A., Aryee, Martin J., Young, Richard A., Crompton, Brian D., Stegmaier, Kimberly, and Massachusetts Institute of Technology. Department of Biology

Abstract

The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer-rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory, and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.

Published
2021

23. STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma

Author

Massachusetts Institute of Technology. Department of Biology, Adane, Biniam, Alexe, Gabriela, Seong, Bo Kyung A., Lu, Diana, Hwang, Elizabeth E., Hnisz, Denes, Lareau, Caleb A., Ross, Linda, Lin, Shan, Dela Cruz, Filemon S., Richardson, Melissa, Weintraub, Abraham Selby, Wang, Sarah, Iniguez, Amanda Balboni, Dharia, Neekesh V., Conway, Amy Saur, Robichaud, Amanda L., Tanenbaum, Benjamin, Krill-Burger, John M., Vazquez, Francisca, Schenone, Monica, Berman, Jason N., Kung, Andrew L., Carr, Steven A., Aryee, Martin J., Young, Richard A., Crompton, Brian D., Stegmaier, Kimberly, Massachusetts Institute of Technology. Department of Biology, Adane, Biniam, Alexe, Gabriela, Seong, Bo Kyung A., Lu, Diana, Hwang, Elizabeth E., Hnisz, Denes, Lareau, Caleb A., Ross, Linda, Lin, Shan, Dela Cruz, Filemon S., Richardson, Melissa, Weintraub, Abraham Selby, Wang, Sarah, Iniguez, Amanda Balboni, Dharia, Neekesh V., Conway, Amy Saur, Robichaud, Amanda L., Tanenbaum, Benjamin, Krill-Burger, John M., Vazquez, Francisca, Schenone, Monica, Berman, Jason N., Kung, Andrew L., Carr, Steven A., Aryee, Martin J., Young, Richard A., Crompton, Brian D., and Stegmaier, Kimberly

Abstract

The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer-rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory, and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.

Published
2021

24. An in vivo CRISPR screening platform for prioritizing therapeutic targets in AML

Author

Lin, Shan, primary, Larrue, Clément, additional, Seong, Bo Kyung A., additional, Dharia, Neekesh V., additional, Kuljanin, Miljan, additional, Wechsler, Caroline, additional, Kugener, Guillaume, additional, Robichaud, Amanda, additional, Conway, Amy, additional, Mashaka, Thelma N., additional, Mouche, Sarah, additional, Adane, Biniam, additional, Ryan, Jeremy, additional, Mancias, Joseph D., additional, Younger, Scott T., additional, Piccioni, Federica, additional, Lee, Lynn, additional, Wunderlich, Mark, additional, Letai, Anthony, additional, Tamburini, Jérôme, additional, and Stegmaier, Kimberly, additional

Published
2020
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25. Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia

Author

Pei, Shanshan, primary, Pollyea, Daniel A., additional, Gustafson, Annika, additional, Stevens, Brett M., additional, Minhajuddin, Mohammad, additional, Fu, Rui, additional, Riemondy, Kent A., additional, Gillen, Austin E., additional, Sheridan, Ryan M., additional, Kim, Jihye, additional, Costello, James C., additional, Amaya, Maria L., additional, Inguva, Anagha, additional, Winters, Amanda, additional, Ye, Haobin, additional, Krug, Anna, additional, Jones, Courtney L., additional, Adane, Biniam, additional, Khan, Nabilah, additional, Ponder, Jessica, additional, Schowinsky, Jeffrey, additional, Abbott, Diana, additional, Hammes, Andrew, additional, Myers, Jason R., additional, Ashton, John M., additional, Nemkov, Travis, additional, D'Alessandro, Angelo, additional, Gutman, Jonathan A., additional, Ramsey, Haley E., additional, Savona, Michael R., additional, Smith, Clayton A., additional, and Jordan, Craig T., additional

Published
2020
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26. Developmental Plasticity of Acute Myeloid Leukemia Mediates Resistance to Venetoclax-Based Therapy

Author

Pei, Shanshan, primary, Pollyea, Daniel A, primary, Gustafson, Annika, primary, Minhajuddin, Mohammad, primary, Stevens, Brett M., primary, Ye, Haobin, primary, Inguva, Anagha, primary, Amaya, Maria L, primary, Krug, Anna, primary, Jones, Courtney L, primary, Adane, Biniam, primary, Winters, Amanda, primary, Khan, Nabilah, primary, Ponder, Jessica, primary, Schowinsky, Jeffrey, primary, Hammes, Andrew, primary, Abbott, Diana, primary, Myers, Jason R, primary, Ashton, John M, primary, Gutman, Jonathan A, primary, Purev, Enkhtsetseg, primary, Ramsey, Haley E., primary, Savona, Michael R., primary, Fesik, Stephen W., primary, Smith, Clayton, primary, and Jordan, Craig T, primary

Published
2019
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28. Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis

Author

Hernandez, Giovanny, primary, Mills, Taylor S., additional, Rabe, Jennifer L., additional, Chavez, James S., additional, Kuldanek, Susan, additional, Kirkpatrick, Gregory, additional, Noetzli, Leila, additional, Jubair, Widian K., additional, Zanche, Michelle, additional, Myers, Jason R., additional, Stevens, Brett M., additional, Fleenor, Courtney J., additional, Adane, Biniam, additional, Dinarello, Charles A., additional, Ashton, John, additional, Jordan, Craig T., additional, Di Paola, Jorge, additional, Hagman, James R., additional, Holers, V. Michael, additional, Kuhn, Kristine A., additional, and Pietras, Eric M., additional

Published
2019
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29. The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells

Author

Adane, Biniam, primary, Ye, Haobin, additional, Khan, Nabilah, additional, Pei, Shanshan, additional, Minhajuddin, Mohammad, additional, Stevens, Brett M., additional, Jones, Courtney L., additional, D’Alessandro, Angelo, additional, Reisz, Julie A., additional, Zaberezhnyy, Vadym, additional, Gasparetto, Maura, additional, Ho, Tzu-Chieh, additional, Kelly, Kathleen K., additional, Myers, Jason R., additional, Ashton, John M., additional, Siegenthaler, Julie, additional, Kume, Tsutomu, additional, Campbell, Eric L., additional, Pollyea, Daniel A., additional, Becker, Michael W., additional, and Jordan, Craig T., additional

Published
2019
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30. Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells

Author

Jones, Courtney L., primary, Stevens, Brett M., additional, D’Alessandro, Angelo, additional, Reisz, Julie A., additional, Culp-Hill, Rachel, additional, Nemkov, Travis, additional, Pei, Shanshan, additional, Khan, Nabilah, additional, Adane, Biniam, additional, Ye, Haobin, additional, Krug, Anna, additional, Reinhold, Dominik, additional, Smith, Clayton, additional, DeGregori, James, additional, Pollyea, Daniel A., additional, and Jordan, Craig T., additional

Published
2019
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31. Rheumatoid Arthritis Causes Hematopoietic Stem Cell Reprogramming to Maintain Functionality

Author

Mills, Taylor, primary, Hernandez, Giovanny, additional, Rabe, Jennifer L, additional, Kuldanek, Susan, additional, Chavez, James, additional, Kirkpatrick, Greg, additional, Noetzli, Leila, additional, Jubair, Widian, additional, Zanche, Michelle, additional, Myers, Jason R, additional, Stevens, Brett M., additional, Fleenor, Courtney, additional, Adane, Biniam, additional, Ashton, John M, additional, Jordan, Craig T, additional, Hagman, James, additional, Di Paola, Jorge, additional, Holers, Michael, additional, Kuhn, Kristine, additional, and Pietras, Eric, additional

Published
2018
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33. Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells

Author

Jones, Courtney L, primary, Stevens, Brett M, additional, D'Alessandro, Angelo, additional, Reisz, Julia, additional, Culp-Hill, Rachel, additional, Nemkov, Travis, additional, Pei, Shanshan, additional, Khan, Nabilah, additional, Adane, Biniam, additional, Ye, Haobin, additional, Reinhold, Dominik, additional, Smith, Clayton, additional, DeGregori, James, additional, Pollyea, Daniel A, additional, and Jordan, Craig T, additional

Published
2018
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34. Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells

Author

Jones, Courtney L., primary, Stevens, Brett M., additional, D'Alessandro, Angelo, additional, Reisz, Julie A., additional, Culp-Hill, Rachel, additional, Nemkov, Travis, additional, Pei, Shanshan, additional, Khan, Nabilah, additional, Adane, Biniam, additional, Ye, Haobin, additional, Krug, Anna, additional, Reinhold, Dominik, additional, Smith, Clayton, additional, DeGregori, James, additional, Pollyea, Daniel A., additional, and Jordan, Craig T., additional

Published
2018
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35. Altered HSC fate underlies aberrant blood phenotypes in rheumatoid arthritis

Author

Pietras, Eric, primary, Hernandez, Giovanny, additional, Kuldanek, Susan, additional, Jennifer, Rabe, additional, Kirkpatrick, Gregory, additional, Noetzli, Leila, additional, Acharya, Sumitra, additional, Adane, Biniam, additional, Jordan, Craig, additional, DiPaola, Jorge, additional, Holers, Michael, additional, and Banda, Nirmal, additional

Published
2017
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39. Rational design of a parthenolide-based drug regimen that selectively eradicates acute myelogenous leukemia stem cells.

Author

Pei, Shanshan, primary, Minhajuddin, Mohammad, additional, D'Alessandro, Angelo, additional, Nemkov, Travis, additional, Stevens, Brett M., additional, Adane, Biniam, additional, Khan, Nabilah, additional, Hagen, Fred K., additional, Yadav, Vinod K., additional, De, Subhajyoti, additional, Ashton, John M., additional, Hansen, Kirk C., additional, Gutman, Jonathan A., additional, Pollyea, Daniel A., additional, Crooks, Peter A., additional, Smith, Clayton, additional, and Jordan, Craig T., additional

Published
2016
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40. Functional Dissection of Cellular Programs to Uncover Novel Gene Dependencies in AML

Author

Ellegast, Jana M, Alexe, Gabriela, Baniya, Subha, Hamze, Amanda, Taillon, Audrey, Adane, Biniam, Saur Conway, Amy, Zhang, Tinghu, Gray, Nathanael S, Armstrong, Scott A, and Stegmaier, Kimberly

Abstract

Genome-scale CRISPR-Cas9 screens have the power to unveil the Achilles' heel of neoplastic cells. Typically, analyses of such large-scale data sets focus on single gene dependencies. An alternative strategy is to evaluate functional networks enriched in a disease or molecular subset of interest. We applied this strategy to the Broad Institute's Cancer Dependency Map (DepMap) data set consisting of genome-scale CRISPR-Cas9 screens in over 1000 cancer cell line models. We hypothesized that interrogating enriched pathways with context-specific dependencies leads to the discovery of functionally informed gene dependencies.

Published
2023
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41. Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche

Author

Ye, Haobin, primary, Adane, Biniam, additional, Khan, Nabilah, additional, Sullivan, Timothy, additional, Minhajuddin, Mohammad, additional, Gasparetto, Maura, additional, Stevens, Brett, additional, Pei, Shanshan, additional, Balys, Marlene, additional, Ashton, John M., additional, Klemm, Dwight J., additional, Woolthuis, Carolien M., additional, Stranahan, Alec W., additional, Park, Christopher Y., additional, and Jordan, Craig T., additional

Published
2016
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47. Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells.

Author

Ye, Haobin, Adane, Biniam, Khan, Nabilah, Alexeev, Erica, Nusbacher, Nichole, Minhajuddin, Mohammad, Stevens, Brett M., Winters, Amanda C., Lin, Xi, Ashton, John M., Purev, Enkhtsetseg, Xing, Lianping, Pollyea, Daniel A., Lozupone, Catherine A., Serkova, Natalie J., Colgan, Sean P., and Jordan, Craig T.

Subjects
*GLUCOSE metabolism, *CANCER cell growth, *INSULIN resistance, *LEUKEMIA treatment, *CANCER invasiveness
Abstract

Summary From an organismal perspective, cancer cell populations can be considered analogous to parasites that compete with the host for essential systemic resources such as glucose. Here, we employed leukemia models and human leukemia samples to document a form of adaptive homeostasis, where malignant cells alter systemic physiology through impairment of both host insulin sensitivity and insulin secretion to provide tumors with increased glucose. Mechanistically, tumor cells induce high-level production of IGFBP1 from adipose tissue to mediate insulin sensitivity. Further, leukemia-induced gut dysbiosis, serotonin loss, and incretin inactivation combine to suppress insulin secretion. Importantly, attenuated disease progression and prolonged survival are achieved through disruption of the leukemia-induced adaptive homeostasis. Our studies provide a paradigm for systemic management of leukemic disease. Graphical Abstract Highlights • Leukemia subverts systemic glucose metabolism by induction of insulin resistance (IR) • Aberrancies in adipose tissue, pancreas, gut, and microbiota contribute to IR • Leukemic progression is attenuated by modulations of systemic glucose metabolism • Leukemia patients display characteristics of IR Ye et al. show that leukemia cells hijack host glucose by inducing IGFBP1 production from adipose tissue to mediate insulin sensitivity and by inducing gut dysbiosis, serotonin loss, and incretin inactivation to suppress insulin secretion. Disrupting this adaptive homeostasis attenuates leukemia progression. [ABSTRACT FROM AUTHOR]

Published
2018
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48. Altered HSC Programming Drives Aberrant Blood Output Underlying RA Pathogenesis

Author

Mills, Taylor, Hernandez, Giovany, Kuldanek, Susan, Rabe, Jennifer L, Kirkpatrick, Greg, Noetzli, Leila, Severs, Erin, Ir, Diana, Acharya, Sumitra, Adane, Biniam, Jordan, Craig T., Di Paola, Jorge, Frank, Daniel, Kuhn, Kristine, Holers, Michael, Banda, Nirmal, and Pietras, Eric Martin

Abstract

Rheumatoid arthritis (RA) is a debilitating autoimmune disorder characterized by autoantibody production towards collagen type-II in the synovial joints of the skeletal system, leading to progressive joint damage. RA is accompanied by chronic systemic production of pro-inflammatory cytokines including IL-6, TNF, and IL-1. Importantly, RA patients often suffer from significant hematological complications including production of tissue-damaging macrophages, chronic anemia, impaired lymphopoiesis and suppressed bone marrow function. As blood-forming hematopoietic stem cells (HSC) constitute the root of the immune system, identifying mechanisms by which altered HSC function may contribute to disease could provide key insights into RA pathogenesis and therapeutic intervention.

Published
2017
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49. Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells.

Author

Shanshan Pei, Minhajuddin, Mohammad, D'Alessandro, Angelo, Nemkov, Travis, Stevens, Brett M., Adane, Biniam, Khan, Nabilah, Hagen, Fred K., Yadav, Vinod K., De, Subhajyoti, Ashton, John M., Hansen, Kirk C., Gutman, Jonathan A., Pollyea, Daniel A., Crooks, Peter A., Smith, Clayton, and Jordan, Craig T.

Subjects
*ACUTE myeloid leukemia treatment, *SESQUITERPENE lactones, *CANCER stem cells, *DRUG design, *METABOLOMICS
Abstract

Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens. [ABSTRACT FROM AUTHOR]

Published
2016
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50. EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes.

Author

Huang Y, Durall RT, Luong NM, Hertzler HJ, Huang J, Gokhale PC, Leeper BA, Persky NS, Root DE, Anekal PV, Montero Llopis PDLM, David CN, Kutok JL, Raimondi A, Saluja K, Luo J, Zahnow CA, Adane B, Stegmaier K, Hawkins CE, Ponne C, Le Q, Shapiro GI, Lemieux ME, Eagen KP, and French CA

Abstract

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUT's ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes. CDKN2A was identified as the only gene amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined EZH2 inhibition and BET inhibition synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort., Statement of Significance: Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.

Published
2023
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