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TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently

Acute myeloid leukemia (AML) generally has an unsatisfactory prognosis despite the recent introduction of new regimens, including targeted agents and antibodies. To find a new druggable pathway, we performed integrated bioinformatic pathway screening on large OHSU and MILE AML databases, discovered...

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Autores principales: Kim, Han Sun, Kim, Bo-Reum, Dao, Thien T. P., Kim, Jin-Mo, Kim, Yoon-Ju, Son, Hyunsong, Jo, Sihyang, Kim, Doyeon, Kim, Jiwoo, Suh, Young Ju, Kim, Hee-Je, Cho, Byung-Sik, Park, Sunghyouk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338213/
https://www.ncbi.nlm.nih.gov/pubmed/36809797
http://dx.doi.org/10.1182/bloodadvances.2022007956
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author Kim, Han Sun
Kim, Bo-Reum
Dao, Thien T. P.
Kim, Jin-Mo
Kim, Yoon-Ju
Son, Hyunsong
Jo, Sihyang
Kim, Doyeon
Kim, Jiwoo
Suh, Young Ju
Kim, Hee-Je
Cho, Byung-Sik
Park, Sunghyouk
author_facet Kim, Han Sun
Kim, Bo-Reum
Dao, Thien T. P.
Kim, Jin-Mo
Kim, Yoon-Ju
Son, Hyunsong
Jo, Sihyang
Kim, Doyeon
Kim, Jiwoo
Suh, Young Ju
Kim, Hee-Je
Cho, Byung-Sik
Park, Sunghyouk
author_sort Kim, Han Sun
collection PubMed
description Acute myeloid leukemia (AML) generally has an unsatisfactory prognosis despite the recent introduction of new regimens, including targeted agents and antibodies. To find a new druggable pathway, we performed integrated bioinformatic pathway screening on large OHSU and MILE AML databases, discovered the SUMOylation pathway, and validated it independently with an external data set (totaling 2959 AML and 642 normal sample data). The clinical relevance of SUMOylation in AML was supported by its core gene expression which is correlated with patient survival, European LeukemiaNet 2017 risk classification, and AML-relevant mutations. TAK-981, a first-in-class SUMOylation inhibitor currently under clinical trials for solid tumors, showed antileukemic effects with apoptosis induction, cell-cycle arrest, and induction of differentiation marker expression in leukemic cells. It exhibited potent nanomolar activity, often stronger than that of cytarabine, which is part of the standard of care. TAK-981’s utility was further demonstrated in in vivo mouse and human leukemia models as well as patient-derived primary AML cells. Our results also indicate direct and cancer cell-inherent anti-AML effects by TAK-981, different from the type 1 interferon and immune-dependent mechanism in a previous solid tumor study. Overall, we provide a proof-of-concept for SUMOylation as a new targetable pathway in AML and propose TAK-981 as a promising direct anti-AML agent. Our data should prompt studies on optimal combination strategies and transitions to clinical trials in AML.
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spelling pubmed-103382132023-07-14 TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently Kim, Han Sun Kim, Bo-Reum Dao, Thien T. P. Kim, Jin-Mo Kim, Yoon-Ju Son, Hyunsong Jo, Sihyang Kim, Doyeon Kim, Jiwoo Suh, Young Ju Kim, Hee-Je Cho, Byung-Sik Park, Sunghyouk Blood Adv Myeloid Neoplasia Acute myeloid leukemia (AML) generally has an unsatisfactory prognosis despite the recent introduction of new regimens, including targeted agents and antibodies. To find a new druggable pathway, we performed integrated bioinformatic pathway screening on large OHSU and MILE AML databases, discovered the SUMOylation pathway, and validated it independently with an external data set (totaling 2959 AML and 642 normal sample data). The clinical relevance of SUMOylation in AML was supported by its core gene expression which is correlated with patient survival, European LeukemiaNet 2017 risk classification, and AML-relevant mutations. TAK-981, a first-in-class SUMOylation inhibitor currently under clinical trials for solid tumors, showed antileukemic effects with apoptosis induction, cell-cycle arrest, and induction of differentiation marker expression in leukemic cells. It exhibited potent nanomolar activity, often stronger than that of cytarabine, which is part of the standard of care. TAK-981’s utility was further demonstrated in in vivo mouse and human leukemia models as well as patient-derived primary AML cells. Our results also indicate direct and cancer cell-inherent anti-AML effects by TAK-981, different from the type 1 interferon and immune-dependent mechanism in a previous solid tumor study. Overall, we provide a proof-of-concept for SUMOylation as a new targetable pathway in AML and propose TAK-981 as a promising direct anti-AML agent. Our data should prompt studies on optimal combination strategies and transitions to clinical trials in AML. The American Society of Hematology 2023-02-24 /pmc/articles/PMC10338213/ /pubmed/36809797 http://dx.doi.org/10.1182/bloodadvances.2022007956 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Myeloid Neoplasia
Kim, Han Sun
Kim, Bo-Reum
Dao, Thien T. P.
Kim, Jin-Mo
Kim, Yoon-Ju
Son, Hyunsong
Jo, Sihyang
Kim, Doyeon
Kim, Jiwoo
Suh, Young Ju
Kim, Hee-Je
Cho, Byung-Sik
Park, Sunghyouk
TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently
title TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently
title_full TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently
title_fullStr TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently
title_full_unstemmed TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently
title_short TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently
title_sort tak-981, a sumoylation inhibitor, suppresses aml growth immune-independently
topic Myeloid Neoplasia
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338213/
https://www.ncbi.nlm.nih.gov/pubmed/36809797
http://dx.doi.org/10.1182/bloodadvances.2022007956
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