PLCG1 is required for AML1-ETO leukemia stem cell self-renewal

Tina M Schnoeder, Adrian Schwarzer, Ashok Kumar Jayavelu, Chen-Jen Hsu, Joanna Kirkpatrick, Konstanze Döhner, Florian Perner, Theresa Eifert, Nicolas Huber, Patricia Arreba-Tutusaus, Anna Dolnik, Salam A Assi, Monica Nafria, Lu Jiang, Yu-Ting Dai, Zhu Chen, Sai-Juan Chen, Sophie G Kellaway, Anetta Ptasinska, Elizabeth S NgEdouard G Stanley, Andrew G Elefanty, Marcus Buschbeck, Holger Bierhoff, Steffen Brodt, Georg Matziolis, Klaus-Dieter Fischer, Andreas Hochhaus, Chun-Wei Chen, Olaf Heidenreich, Matthias Mann, Steven W Lane, Lars Bullinger, Alessandro Ori, Björn von Eyss, Constanze Bonifer, Florian H Heidel

Research output: Contribution to journalArticlepeer-review

Abstract

In an effort to identify novel drugs targeting fusion-oncogene-induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE)-driven AML, we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein that is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO+ leukemic stem cells.

Original languageEnglish
Pages (from-to)1080-1097
Number of pages18
JournalBlood
Volume139
Issue number7
DOIs
Publication statusPublished - 17 Feb 2022

Keywords

  • Animals
  • Cell Self Renewal
  • Core Binding Factor Alpha 2 Subunit/genetics
  • Gene Expression Regulation, Leukemic
  • Hematopoietic Stem Cells/metabolism
  • Humans
  • Leukemia, Myeloid, Acute/genetics
  • Mice
  • Neoplastic Stem Cells/metabolism
  • Oncogene Proteins, Fusion/genetics
  • Phospholipase C gamma/genetics
  • Proteome
  • RUNX1 Translocation Partner 1 Protein/genetics
  • Transcriptome
  • Translocation, Genetic

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