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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2018
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.
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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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