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

Author:

Patnana Pradeep Kumar123ORCID,Liu Longlong14,Frank Daria12,Nimmagadda Subbaiah Chary13,Behrens Matthias5,Ahmed Helal13,Xie Xiaoqing16,Liebmann Marie7,Wei Lanying18,Gerdemann Andrea5,Thivakaran Aniththa9,Humpf Hans‐Ulrich5,Klotz Luisa7,Dugas Martin10,Varghese Julian8,Trajkovic‐Arsic Marija1112,Siveke Jens T.1112,Hanenberg Helmut913,Opalka Bertram2,Dührsen Ulrich2ORCID,Reinhardt Hans Christian2,Guenther Ulrich14,von Bubnoff Nikolas3,Khandanpour Cyrus123ORCID

Affiliation:

1. Department of Medicine A, Hematology, Oncology and Pneumology University Hospital Muenster Muenster Germany

2. Department of Hematology and Stem Cell Transplantation University Hospital Essen, University of Duisburg‐Essen Essen Germany

3. Department of Hematology and Oncology University Hospital of Schleswig‐Holstein, University of Lübeck Lübeck Germany

4. Department of Hematology, First Affiliated Hospital Guangzhou Medical University Guangzhou China

5. Institute of Food Chemistry, University of Muenster Muenster Germany

6. Department of Hematology‐Oncology Chongqing University Cancer Hospital Chongqing China

7. Department of Neurology with Institute of Translational Neurology, University Hospital Muenster Muenster Germany

8. Institute of Medical Informatics, University of Muenster Muenster Germany

9. Clinic for Pediatrics III, University Hospital Essen Essen Germany

10. Institute of Medical Informatics, Heidelberg University Hospital Heidelberg Germany

11. Bridge Institute of Experimental Tumor Therapy, West German Cancer Center University Hospital Essen, University of Duisburg‐Essen Essen Germany

12. Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center, DKFZ Heidelberg Germany

13. Pediatric Oncology, Hematology & Immunology Heinrich Heine University, University Hospital Düsseldorf Dusseldorf Germany

14. Institute of Chemistry and Metabolomics, University of Lübeck Lübeck Germany

Abstract

SummaryGrowth 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.

Funder

Deutsche Forschungsgemeinschaft

Deutsche Krebshilfe

Publisher

Wiley

Subject

Hematology

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