Dose-dependent expression of GFI1 alters metabolism in the haematopoietic progenitors and MLL::AF9-induced leukaemic cells

Pradeep Kumar Patnana, Longlong Liu, Daria Frank, Subbaiah Chary Nimmagadda, Matthias Behrens, Helal Ahmed, Xiaoqing Xie, Marie Liebmann, Lanying Wei, Andrea Gerdemann, Aniththa Thivakaran, Hans Ulrich Humpf, Luisa Klotz, Martin Dugas, Julian Varghese, Marija Trajkovic-Arsic, Jens T. Siveke, Helmut Hanenberg, Bertram Opalka, Ulrich DührsenHans Christian Reinhardt, Ulrich Guenther, Nikolas von Bubnoff, Cyrus Khandanpour*

*Corresponding author for this work

Abstract

Growth factor independence 1 (GFI1) is a transcriptional repressor protein that plays an essential role in the differentiation of myeloid and lymphoid progenitors. We and other groups have shown that GFI1 has a dose-dependent role in the initiation, progression, and prognosis of acute myeloid leukaemia (AML) patients by inducing epigenetic changes. We now demonstrate a novel role for dose-dependent GFI1 expression in regulating metabolism in haematopoietic progenitor and leukaemic cells. Using in-vitro and ex-vivo murine models of MLL::AF9-induced human AML and extra-cellular flux assays, we now demonstrate that a lower GFI1 expression enhances oxidative phosphorylation rate via upregulation of the FOXO1- MYC axis. Our findings underscore the significance of therapeutic exploitation in GFI1-low-expressing leukaemia cells by targeting oxidative phosphorylation and glutamine metabolism.

Original languageEnglish
JournalBritish Journal of Haematology
Volume202
Issue number5
Pages (from-to)1033-1048
Number of pages16
ISSN0007-1048
DOIs
Publication statusPublished - 09.2023

Research Areas and Centers

  • Research Area: Luebeck Integrated Oncology Network (LION)
  • Centers: University Cancer Center Schleswig-Holstein (UCCSH)

DFG Research Classification Scheme

  • 205-14 Haematology, Oncology

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