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

Patnana P.K.; Liu L.; Frank D.; Nimmagadda S.; Behrens M.; Ahmed H.; Xie X.; Liebmann M.; Wei L.; Gerdemann A.; Thivakaran A.; Humpf H.U.; Klotz L.; Dugas M.; Varghese J.; Trajkovic-Arsic M.; Siveke J.T.; Hanenberg H.; Opalka B.; Dührsen U.; Reinhardt H.C.; Guenther U.; von Bubnoff N.; Khandanpour C.

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.