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

Feder, Kristin; Edmaier-Schroeger, Katrin; Rawat, Vijay P. S.; Kirsten, Nicole; Metzeler, Klaus; Kraus, Johann M.; Doehner, Konstanze; Doehner, Hartmut; Kestler, Hans A.; Feuring-Buske, Michaela und Buske, Christian (2020): Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis. In: Leukemia, Bd. 34, Nr. 4: S. 1027-1037

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 naive normal karyotype AML as well as samples AML LSCs predominantly express the long beta-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 beta-catenin-binding site. Gene expression and ChiP-Seq analyses in mice linked the long isoform to Wnt-beta-catenin signaling and oncogenic pathways, the N-terminally truncated isoform to stemness associated genes. Approaches impairing binding of LEF1 to beta-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 beta-catenin/LEF1 interaction.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0887-6924
• Sprache: Englisch