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Molecular targets for therapy

The transcriptional regulator FUBP1 influences disease outcome in murine and human myeloid leukemia

Leukemia volume 33, pages 1700–1712 (2019)Cite this article

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Abstract

The transcriptional regulator far upstream element binding protein 1 (FUBP1) acts as an oncoprotein in solid tumor entities and plays a role in the maintenance of hematopoietic stem cells. However, its potential function in leukemia is unknown. In murine models of chronic (CML) and acute myeloid leukemia (AML) induced by BCR-ABL1 and MLL-AF9, respectively, knockdown of Fubp1 resulted in prolonged survival, decreased numbers of CML progenitor cells, decreased cell cycle activity and increased apoptosis. Knockdown of FUBP1 in CML and AML cell lines recapitulated these findings and revealed enhanced DNA damage compared to leukemia cells expressing wild type FUBP1 levels. FUBP1 was more highly expressed in human CML compared to normal bone marrow cells and its expression correlated with disease progression. In AML, higher FUBP1 expression in patient leukemia cells was observed with a trend toward correlation with shorter overall survival. Treatment of mice with AML with irinotecan, known to inhibit topoisomerase I and FUBP1, significantly prolonged survival alone or in combination with cytarabine. In summary, our data suggest that FUBP1 acts as cell cycle regulator and apoptosis inhibitor in leukemia. We demonstrated that FUBP1 might play a role in DNA repair, and its inhibition may improve outcome in leukemia patients.

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Acknowledgements

This work was supported by grant 2015.039.1 to MZ and DSK from the Wilhelm Sander-Stiftung.We thank the Serviceeinrichtung Transkriptomanalyselabor (TAL) in Göttingen, Germany, for performing the RNA sequencing work.

Author contributions

VTH designed and carried out experiments, analyzed the data and wrote a first draft of the manuscript. DV designed and carried out experiments and analyzed the data. SG, PL, MS, KG, EW and UM-K assisted with experiments. BM and HF assisted with the analysis of the RNA-sequencing data. HB, TO, and AW provided and analyzed the human immunohistochemical data. JMV and VGO provided and analyzed the human genomic datasets. MZ and DSK designed experiments, supervised the project and analyzed data. DSK wrote the manuscript.

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Author notes

  1. These authors contributed equally: Van T. Hoang, Divij Verma

  2. These authors contributed equally: Martin Zörnig, Daniela S. Krause

Authors and Affiliations

  1. Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany

    Van T. Hoang, Divij Verma, Parimala Sonika Godavarthy, Pablo Llavona, Marlene Steiner, Katharina Gerlach, Birgitta E. Michels, Uta Müller-Kuller, Eva Weissenberger, Henner F. Farin, Martin Zörnig & Daniela S. Krause

  2. German Cancer Consortium (DKTK), Heidelberg, Germany

    Birgitta E. Michels, Thomas Oellerich, Henner F. Farin & Daniela S. Krause

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Birgitta E. Michels, Thomas Oellerich, Henner F. Farin & Daniela S. Krause

  4. Faculty of Biological Sciences, Goethe University Frankfurt, Frankfurt, Germany

    Birgitta E. Michels

  5. Universitätsmedizin Göttingen, Institute of Pathology, Georg-August-Universität, 37075, Göttingen, Germany

    Hanibal Bohnenberger

  6. Universitätsmedizin Göttingen, Department of Medical Statistics, Georg-August-Universität, 37075, Göttingen, Germany

    Astrid Wachter

  7. University Hospital Frankfurt, Department of Medicine II, Hematology/Oncology, Frankfurt, Germany

    Thomas Oellerich

  8. Fred Hutchinson Cancer Research Center, Clinical Research Division, Biostatistics, Seattle, WA, USA

    Jenna M. Voutsinas

  9. Fred Hutchinson Cancer Research Center, Clinical Research Division, Division of Hematology, University of Washington Medical Center, Seattle, WA, USA

    Vivian G. Oehler

  10. Faculty of Medicine, Johann Wolfgang Goethe University, Frankfurt, Germany

    Daniela S. Krause

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Hoang, V.T., Verma, D., Godavarthy, P.S. et al. The transcriptional regulator FUBP1 influences disease outcome in murine and human myeloid leukemia. Leukemia 33, 1700–1712 (2019). https://doi.org/10.1038/s41375-018-0358-8

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