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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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.
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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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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