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Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia
Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This i...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102195/ https://www.ncbi.nlm.nih.gov/pubmed/33531656 http://dx.doi.org/10.1038/s41375-021-01132-5 |
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author | Ge, Zheng Song, Chunhua Ding, Yali Tan, Bi-Hua Desai, Dhimant Sharma, Arati Gowda, Raghavendra Yue, Feng Huang, Suming Spiegelman, Vladimir Payne, Jonathon L. Reeves, Mark E. Iyer, Soumya Dhanyamraju, Pavan Kumar Imamura, Yuka Bogush, Daniel Bamme, Yevgeniya Yang, Yiping Soliman, Mario Kane, Shriya Dovat, Elanora Schramm, Joseph Hu, Tommy McGrath, Mary Chroneos, Zissis C. Payne, Kimberly J. Gowda, Chandrika Dovat, Sinisa |
author_facet | Ge, Zheng Song, Chunhua Ding, Yali Tan, Bi-Hua Desai, Dhimant Sharma, Arati Gowda, Raghavendra Yue, Feng Huang, Suming Spiegelman, Vladimir Payne, Jonathon L. Reeves, Mark E. Iyer, Soumya Dhanyamraju, Pavan Kumar Imamura, Yuka Bogush, Daniel Bamme, Yevgeniya Yang, Yiping Soliman, Mario Kane, Shriya Dovat, Elanora Schramm, Joseph Hu, Tommy McGrath, Mary Chroneos, Zissis C. Payne, Kimberly J. Gowda, Chandrika Dovat, Sinisa |
author_sort | Ge, Zheng |
collection | PubMed |
description | Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS’ ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies. |
format | Online Article Text |
id | pubmed-8102195 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81021952021-05-24 Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia Ge, Zheng Song, Chunhua Ding, Yali Tan, Bi-Hua Desai, Dhimant Sharma, Arati Gowda, Raghavendra Yue, Feng Huang, Suming Spiegelman, Vladimir Payne, Jonathon L. Reeves, Mark E. Iyer, Soumya Dhanyamraju, Pavan Kumar Imamura, Yuka Bogush, Daniel Bamme, Yevgeniya Yang, Yiping Soliman, Mario Kane, Shriya Dovat, Elanora Schramm, Joseph Hu, Tommy McGrath, Mary Chroneos, Zissis C. Payne, Kimberly J. Gowda, Chandrika Dovat, Sinisa Leukemia Article Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS’ ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies. Nature Publishing Group UK 2021-02-02 2021 /pmc/articles/PMC8102195/ /pubmed/33531656 http://dx.doi.org/10.1038/s41375-021-01132-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ge, Zheng Song, Chunhua Ding, Yali Tan, Bi-Hua Desai, Dhimant Sharma, Arati Gowda, Raghavendra Yue, Feng Huang, Suming Spiegelman, Vladimir Payne, Jonathon L. Reeves, Mark E. Iyer, Soumya Dhanyamraju, Pavan Kumar Imamura, Yuka Bogush, Daniel Bamme, Yevgeniya Yang, Yiping Soliman, Mario Kane, Shriya Dovat, Elanora Schramm, Joseph Hu, Tommy McGrath, Mary Chroneos, Zissis C. Payne, Kimberly J. Gowda, Chandrika Dovat, Sinisa Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia |
title | Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia |
title_full | Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia |
title_fullStr | Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia |
title_full_unstemmed | Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia |
title_short | Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia |
title_sort | dual targeting of mtor as a novel therapeutic approach for high-risk b-cell acute lymphoblastic leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102195/ https://www.ncbi.nlm.nih.gov/pubmed/33531656 http://dx.doi.org/10.1038/s41375-021-01132-5 |
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