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Nuclear FOXM1 drives chemoresistance in AML

Leukemia volume 31, pages 251–255 (2017)Cite this article

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Forkhead box M1 (FOXM1) is a transcription factor of the Forkhead family that induces the expression of genes involved in the execution of the mitotic program.1 FOXM1 is expressed in dividing and transformed/tumor cells, but not in terminally differentiated or quiescent cells and contributes to several aspects of oncogenesis.2 A FOXM1 regulatory network was a major predictor of adverse outcomes in a meta-analysis of expression signatures from ∼18 000 human tumors with overall survival outcomes.3 Also, FOXM1 mRNA was overexpressed in all of 127 examined acute myeloid leukemia (AML) patient samples and immunofluorescence revealed much stronger nuclear FOXM1 expression in leukemic progenitor cells compared with normal counterparts where it was postulated to be driving increased proliferation.4

We have previously shown that FOXM1 co-localizes with nucleophosmin (NPM) in cancer cells and NPM binding is required for the expression of FOXM1.5 NPM, a protein that shuttles between the nucleus and cytoplasm,6 is credited with both oncogenic and tumor-suppressive functions. In 2005, a landmark study7 revealed a mutation localized to exon 12 of NPM1 that characterizes 1/3 of de novo AML cases and results in cytoplasmic relocalization of NPM1 (NPM1mut). Gene expression profiling8 confirmed that NPM1mut AML represents a distinct entity and these patients demonstrate significantly better relapse-free and overall survival after chemotherapy.9, 10 We have also shown by immunofluorescence in the AML cell line OCI-AML3, characterized by the pathogenic NPM1 exon 12 mutation,11 that NPM and FOXM1 co-localize in the cytoplasm.5 In the present study, we hypothesize that improved outcomes in the subset of NPM1mut AML is partly attributable to the cytoplasmic relocalization and consequent inactivation of FOXM1.

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Acknowledgements

We acknowledge the University of Illinois Hematology Cell Bank for the use of viable leukemia patient samples (IRB# 2014-0048; HEMBANK-01). We thank Dr Mark Minden (Ontario Cancer Institute) for the OCI-AML3 leukemia cell line, Dr Pradip Raychaudhuri (UIC) for the α-tubulin antibody and Dr Viswanathan Natarajan (UIC) for the Lamin B1 antibody. We also thank Dr Amit Khanal (UIC), Dr Yoon Sang Kim (UIC) and Dr Binal Shah (UIC) for technical assistance. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000050. This work was supported by NIH grants 5R01CA138409 and 5R21CA194608, and also Bridge Funding Grant from UIC, all to ALG. NIH grant 5 T32 DK007788-14 to MH. This work was also supported by a UIC Cancer Center Pilot Grant awarded jointly to IK and ALG.

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  1. I Khan and M Halasi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology/Oncology, University of Illinois, Chicago, IL, USA

    I Khan, M F Zia & N Mahmud

  2. Division of Gastroenterology/Hepatology, Department of Medicine,University of Illinois, Chicago, IL, USA

    M Halasi & A L Gartel

  3. Division of Research Histology and Tissue Imaging Core, University of Illinois, Chicago, IL, USA

    P Gann & S Gaitonde

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  1. I Khan
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  2. M Halasi
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  6. N Mahmud
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  7. A L Gartel
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Correspondence to I Khan or A L Gartel.

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Khan, I., Halasi, M., Zia, M. et al. Nuclear FOXM1 drives chemoresistance in AML. Leukemia 31, 251–255 (2017). https://doi.org/10.1038/leu.2016.270

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