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FOXM1 contributes to treatment failure in acute myeloid leukemia
Irum Khan, … , Olga Frankfurt, Andrei L. Gartel
Irum Khan, … , Olga Frankfurt, Andrei L. Gartel
Published August 9, 2018
Citation Information: JCI Insight. 2018;3(15):e121583. https://doi.org/10.1172/jci.insight.121583.
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Research Article Hematology Oncology

FOXM1 contributes to treatment failure in acute myeloid leukemia

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Abstract

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.

Authors

Irum Khan, Marianna Halasi, Anand Patel, Rachael Schultz, Nandini Kalakota, Yi-Hua Chen, Nathan Aardsma, Li Liu, John D. Crispino, Nadim Mahmud, Olga Frankfurt, Andrei L. Gartel

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Figure 1

FOXM1 is an independent predictor of chemotherapy resistance in intermediate risk CN-AML.

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FOXM1 is an independent predictor of chemotherapy resistance in intermed...
(A) BM slides were stained with FOXM1 antibody and counterstained with hematoxylin. Utilizing the Aperio AT2 whole slide scanner and HALO 2.0 software, images were analyzed. Two representative patient samples are shown (200× magnification) with high and low percentage of nuclei expressing FOXM1, with the corresponding markup images below that were quantified. (B) In an analysis of the patients who achieved a CR following chemotherapy, there were 74 BM samples with quantifiable FOXM1 expression. We found that patients needing more than 1 cycle of induction therapy had greater than a 2-fold increase in the percentage of nuclei expressing FOXM1 (mean 25.6% vs. 11.4% nuclei, P = 0.004, 2-tailed t test) in their diagnostic BM. (C) Kaplan-Meier analysis for overall survival in 43 patients from a single institution in our cohort, stratified based on average nuclear intensity of FOXM1. FOXM1hi patients had an inferior survival that approached statistical significance (median 501 days vs. not reached, P = 0.068, log rank test).

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