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Acute myeloid leukemia

Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis

Leukemia volume 34, pages 1027–1037 (2020)Cite this article

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Abstract

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is propagated by leukemic stem cells (LSCs), often characterized by deregulated Wnt signaling. We previously showed that the central transcriptional mediator of Wnt signaling LEF1 is able to cause AML in mice and acts as an independent prognostic factor in normal karyotype AML. Here, we show that treatment naïve normal karyotype AML as well as samples AML LSCs predominantly express the long β-catenin-binding isoform of LEF1 in sharp contrast to normal human hematopoietic stem cells, which lack expression of the long isoform, but express the short N-terminally truncated isoform with loss of the β-catenin-binding site. Gene expression and ChiP-Seq analyses in mice linked the long isoform to Wnt-β-catenin signaling and oncogenic pathways, the N-terminally truncated isoform to stemness associated genes. Approaches impairing binding of LEF1 to β-catenin significantly impaired AML growth, but spared normal hematopoietic stem cells. This report now demonstrates a striking difference of LEF1 isoform expression between normal and AML cells, contributing to higher vulnerability of leukemic cells to approaches targeting β-catenin/LEF1 interaction.

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Acknowledgements

The authors would like to thank all members of the Core Facility FACS, Core Facility Genomics of the University Ulm and the animal facility of the Helmholtz Centre Munich and the University Ulm for breeding and maintenance of the animals. The work was supported by the grant from the DFG (SFB 1074 project A4 to KF and CB, A6 to MFB, Z1 to CB, HAK and JMK and B3 to KD) and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – GRK 1789.

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  1. These author contributed equally Kristin Feder, Katrin Edmaier-Schröger

Authors and Affiliations

  1. Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081, Ulm, Germany

    Kristin Feder, Katrin Edmaier-Schröger, Vijay P. S. Rawat, Nicole Kirsten, Michaela Feuring-Buske & Christian Buske

  2. Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany

    Klaus Metzeler

  3. Institute of Medical Systems Biology, Ulm University, 89081, Ulm, Germany

    Johann M. Kraus & Hans A. Kestler

  4. Department of Internal Medicine III, University Hospital Ulm, 89081, Ulm, Germany

    Konstanze Döhner, Hartmut Döhner & Michaela Feuring-Buske

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Feder, K., Edmaier-Schröger, K., Rawat, V.P.S. et al. Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis. Leukemia 34, 1027–1037 (2020). https://doi.org/10.1038/s41375-019-0635-1

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