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FOXM1 contributes to treatment failure in acute myeloid leukemia
Acute myeloid leukemia (AML) patients with NPM1 mutations demonstrate a superior response to standard chemotherapy treatment. Our previous work has shown that these favorable outcomes are linked to the cytoplasmic relocalization and inactivation of FOXM1 driven by mutated NPM1. Here, we went on to c...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129129/ https://www.ncbi.nlm.nih.gov/pubmed/30089730 http://dx.doi.org/10.1172/jci.insight.121583 |
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author | Khan, Irum Halasi, Marianna Patel, Anand Schultz, Rachael Kalakota, Nandini Chen, Yi-Hua Aardsma, Nathan Liu, Li Crispino, John D. Mahmud, Nadim Frankfurt, Olga Gartel, Andrei L. |
author_facet | Khan, Irum Halasi, Marianna Patel, Anand Schultz, Rachael Kalakota, Nandini Chen, Yi-Hua Aardsma, Nathan Liu, Li Crispino, John D. Mahmud, Nadim Frankfurt, Olga Gartel, Andrei L. |
author_sort | Khan, Irum |
collection | PubMed |
description | Acute myeloid leukemia (AML) patients with NPM1 mutations demonstrate a superior response to standard chemotherapy treatment. Our previous work has shown that these favorable outcomes are linked to the cytoplasmic relocalization and inactivation of FOXM1 driven by mutated NPM1. Here, we went on to confirm the important role of FOXM1 in increased chemoresistance in AML. A multiinstitution retrospective study was conducted to link FOXM1 expression to clinical outcomes in AML. We establish nuclear FOXM1 as an independent clinical predictor of chemotherapeutic resistance in intermediate-risk AML in a multivariate analysis incorporating standard clinicopathologic risk factors. Using colony assays, we show a dramatic decrease in colony size and numbers in AML cell lines with knockdown of FOXM1, suggesting an important role for FOXM1 in the clonogenic activity of AML cells. In order to further prove a potential role for FOXM1 in AML chemoresistance, we induced an FLT3-ITD–driven myeloid neoplasm in a FOXM1-overexpressing transgenic mouse model and demonstrated significantly higher residual disease after standard chemotherapy. This suggests that constitutive overexpression of FOXM1 in this model induces chemoresistance. Finally, we performed proof-of-principle experiments using a currently approved proteasome inhibitor, ixazomib, to target FOXM1 and demonstrated a therapeutic response in AML patient samples and animal models of AML that correlates with the suppression of FOXM1 and its transcriptional targets. Addition of low doses of ixazomib increases sensitization of AML cells to chemotherapy backbone drugs cytarabine and the hypomethylator 5-azacitidine. Our results underscore the importance of FOXM1 in AML progression and treatment, and they suggest that targeting it may have therapeutic benefit in combination with standard AML therapies. |
format | Online Article Text |
id | pubmed-6129129 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-61291292018-09-14 FOXM1 contributes to treatment failure in acute myeloid leukemia Khan, Irum Halasi, Marianna Patel, Anand Schultz, Rachael Kalakota, Nandini Chen, Yi-Hua Aardsma, Nathan Liu, Li Crispino, John D. Mahmud, Nadim Frankfurt, Olga Gartel, Andrei L. JCI Insight Research Article Acute myeloid leukemia (AML) patients with NPM1 mutations demonstrate a superior response to standard chemotherapy treatment. Our previous work has shown that these favorable outcomes are linked to the cytoplasmic relocalization and inactivation of FOXM1 driven by mutated NPM1. Here, we went on to confirm the important role of FOXM1 in increased chemoresistance in AML. A multiinstitution retrospective study was conducted to link FOXM1 expression to clinical outcomes in AML. We establish nuclear FOXM1 as an independent clinical predictor of chemotherapeutic resistance in intermediate-risk AML in a multivariate analysis incorporating standard clinicopathologic risk factors. Using colony assays, we show a dramatic decrease in colony size and numbers in AML cell lines with knockdown of FOXM1, suggesting an important role for FOXM1 in the clonogenic activity of AML cells. In order to further prove a potential role for FOXM1 in AML chemoresistance, we induced an FLT3-ITD–driven myeloid neoplasm in a FOXM1-overexpressing transgenic mouse model and demonstrated significantly higher residual disease after standard chemotherapy. This suggests that constitutive overexpression of FOXM1 in this model induces chemoresistance. Finally, we performed proof-of-principle experiments using a currently approved proteasome inhibitor, ixazomib, to target FOXM1 and demonstrated a therapeutic response in AML patient samples and animal models of AML that correlates with the suppression of FOXM1 and its transcriptional targets. Addition of low doses of ixazomib increases sensitization of AML cells to chemotherapy backbone drugs cytarabine and the hypomethylator 5-azacitidine. Our results underscore the importance of FOXM1 in AML progression and treatment, and they suggest that targeting it may have therapeutic benefit in combination with standard AML therapies. American Society for Clinical Investigation 2018-08-09 /pmc/articles/PMC6129129/ /pubmed/30089730 http://dx.doi.org/10.1172/jci.insight.121583 Text en Copyright © 2018 Khan et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Khan, Irum Halasi, Marianna Patel, Anand Schultz, Rachael Kalakota, Nandini Chen, Yi-Hua Aardsma, Nathan Liu, Li Crispino, John D. Mahmud, Nadim Frankfurt, Olga Gartel, Andrei L. FOXM1 contributes to treatment failure in acute myeloid leukemia |
title | FOXM1 contributes to treatment failure in acute myeloid leukemia |
title_full | FOXM1 contributes to treatment failure in acute myeloid leukemia |
title_fullStr | FOXM1 contributes to treatment failure in acute myeloid leukemia |
title_full_unstemmed | FOXM1 contributes to treatment failure in acute myeloid leukemia |
title_short | FOXM1 contributes to treatment failure in acute myeloid leukemia |
title_sort | foxm1 contributes to treatment failure in acute myeloid leukemia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129129/ https://www.ncbi.nlm.nih.gov/pubmed/30089730 http://dx.doi.org/10.1172/jci.insight.121583 |
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