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A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction

Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as...

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Autores principales: Somers, Klaartje, Wen, Victoria W., Middlemiss, Shiloh M. C., Osborne, Brenna, Forgham, Helen, Jung, MoonSun, Karsa, Mawar, Clifton, Molly, Bongers, Angelika, Gao, Jixuan, Mayoh, Chelsea, Raoufi-Rad, Newsha, Kusnadi, Eric P., Hannan, Kate M., Scott, David A., Kwek, Alan, Liu, Bing, Flemming, Claudia, Chudakova, Daria A., Pandher, Ruby, Failes, Tim W., Lim, James, Angeli, Andrea, Osterman, Andrei L., Imamura, Toshihiko, Kees, Ursula R., Supuran, Claudiu T., Pearson, Richard B., Hannan, Ross D., Davis, Thomas P., McCarroll, Joshua, Kavallaris, Maria, Turner, Nigel, Gudkov, Andrei V., Haber, Michelle, Norris, Murray D., Henderson, Michelle J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756102/
https://www.ncbi.nlm.nih.gov/pubmed/30670779
http://dx.doi.org/10.1038/s41388-018-0666-5
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author Somers, Klaartje
Wen, Victoria W.
Middlemiss, Shiloh M. C.
Osborne, Brenna
Forgham, Helen
Jung, MoonSun
Karsa, Mawar
Clifton, Molly
Bongers, Angelika
Gao, Jixuan
Mayoh, Chelsea
Raoufi-Rad, Newsha
Kusnadi, Eric P.
Hannan, Kate M.
Scott, David A.
Kwek, Alan
Liu, Bing
Flemming, Claudia
Chudakova, Daria A.
Pandher, Ruby
Failes, Tim W.
Lim, James
Angeli, Andrea
Osterman, Andrei L.
Imamura, Toshihiko
Kees, Ursula R.
Supuran, Claudiu T.
Pearson, Richard B.
Hannan, Ross D.
Davis, Thomas P.
McCarroll, Joshua
Kavallaris, Maria
Turner, Nigel
Gudkov, Andrei V.
Haber, Michelle
Norris, Murray D.
Henderson, Michelle J.
author_facet Somers, Klaartje
Wen, Victoria W.
Middlemiss, Shiloh M. C.
Osborne, Brenna
Forgham, Helen
Jung, MoonSun
Karsa, Mawar
Clifton, Molly
Bongers, Angelika
Gao, Jixuan
Mayoh, Chelsea
Raoufi-Rad, Newsha
Kusnadi, Eric P.
Hannan, Kate M.
Scott, David A.
Kwek, Alan
Liu, Bing
Flemming, Claudia
Chudakova, Daria A.
Pandher, Ruby
Failes, Tim W.
Lim, James
Angeli, Andrea
Osterman, Andrei L.
Imamura, Toshihiko
Kees, Ursula R.
Supuran, Claudiu T.
Pearson, Richard B.
Hannan, Ross D.
Davis, Thomas P.
McCarroll, Joshua
Kavallaris, Maria
Turner, Nigel
Gudkov, Andrei V.
Haber, Michelle
Norris, Murray D.
Henderson, Michelle J.
author_sort Somers, Klaartje
collection PubMed
description Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.
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spelling pubmed-67561022019-09-24 A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction Somers, Klaartje Wen, Victoria W. Middlemiss, Shiloh M. C. Osborne, Brenna Forgham, Helen Jung, MoonSun Karsa, Mawar Clifton, Molly Bongers, Angelika Gao, Jixuan Mayoh, Chelsea Raoufi-Rad, Newsha Kusnadi, Eric P. Hannan, Kate M. Scott, David A. Kwek, Alan Liu, Bing Flemming, Claudia Chudakova, Daria A. Pandher, Ruby Failes, Tim W. Lim, James Angeli, Andrea Osterman, Andrei L. Imamura, Toshihiko Kees, Ursula R. Supuran, Claudiu T. Pearson, Richard B. Hannan, Ross D. Davis, Thomas P. McCarroll, Joshua Kavallaris, Maria Turner, Nigel Gudkov, Andrei V. Haber, Michelle Norris, Murray D. Henderson, Michelle J. Oncogene Article Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells. Nature Publishing Group UK 2019-01-22 2019 /pmc/articles/PMC6756102/ /pubmed/30670779 http://dx.doi.org/10.1038/s41388-018-0666-5 Text en © The Author(s) 2019 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/.
spellingShingle Article
Somers, Klaartje
Wen, Victoria W.
Middlemiss, Shiloh M. C.
Osborne, Brenna
Forgham, Helen
Jung, MoonSun
Karsa, Mawar
Clifton, Molly
Bongers, Angelika
Gao, Jixuan
Mayoh, Chelsea
Raoufi-Rad, Newsha
Kusnadi, Eric P.
Hannan, Kate M.
Scott, David A.
Kwek, Alan
Liu, Bing
Flemming, Claudia
Chudakova, Daria A.
Pandher, Ruby
Failes, Tim W.
Lim, James
Angeli, Andrea
Osterman, Andrei L.
Imamura, Toshihiko
Kees, Ursula R.
Supuran, Claudiu T.
Pearson, Richard B.
Hannan, Ross D.
Davis, Thomas P.
McCarroll, Joshua
Kavallaris, Maria
Turner, Nigel
Gudkov, Andrei V.
Haber, Michelle
Norris, Murray D.
Henderson, Michelle J.
A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
title A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
title_full A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
title_fullStr A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
title_full_unstemmed A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
title_short A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
title_sort novel small molecule that kills a subset of mll-rearranged leukemia cells by inducing mitochondrial dysfunction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756102/
https://www.ncbi.nlm.nih.gov/pubmed/30670779
http://dx.doi.org/10.1038/s41388-018-0666-5
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