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

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 2

FOXM1 confers resistance to standard chemotherapy.

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FOXM1 confers resistance to standard chemotherapy. (A) KG-1 cells were t...
(A) KG-1 cells were treated as indicated. Total cell lysates were analyzed by Western blotting for the level of FOXM1. (B and C) Transgenic FOXM1 overexpressing (FoxM1b Tg;Arf–/–) and control (Arf–/–) animals were treated with 5-FU to enrich for hematopoietic progenitor cells. These cells were transduced with FLT3-ITD retroviral particles and transplanted into syngeneic recipients. Following disease establishment, animals were randomized and treated with vehicle or cytarabine (AraC) for 5 consecutive days. Three weeks after treatment, the BM (B) and the spleens (C) were analyzed for leukemic burden as assessed by GFP measurement by flow cytometry. Data are expressed as the mean ± SEM (n = 4/group); P < 0.05 by unpaired one-tailed t test (B) and unpaired 2-tailed t test (C). (D) FLT3-ITD transformed BM cells (generated and treated as described in B and C) were studied in serial replating colony assays. Representative images of the colonies were imaged with the EVOS XL Core Imaging System using the 4× objective. (E) Plot shows increased colony numbers with the serial replating in the treated FOXM1 overexpressing mice compared with their treated control counterparts. Data are expressed as the mean ± SEM (n = 2) experiments done in triplicate; P < 0.05 by unpaired 2-tailed t test.