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 Dührsen; Hans Christian Reinhardt; Ulrich Guenther; Nikolas von Bubnoff; Cyrus Khandanpour

doi:10.1111/bjh.18939

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

Br J Haematol. 2023 Sep;202(5):1033-1048. doi: 10.1111/bjh.18939. Epub 2023 Jul 9.

Authors

Pradeep Kumar Patnana^{1

2

3}, Longlong Liu^{1

4}, Daria Frank^{1

2}, Subbaiah Chary Nimmagadda^{1

3}, Matthias Behrens⁵, Helal Ahmed^{1

3}, Xiaoqing Xie^{1

6}, Marie Liebmann⁷, Lanying Wei^{1

8}, Andrea Gerdemann⁵, Aniththa Thivakaran⁹, Hans-Ulrich Humpf⁵, Luisa Klotz⁷, Martin Dugas¹⁰, Julian Varghese⁸, Marija Trajkovic-Arsic^{11

12}, Jens T Siveke^{11

12}, Helmut Hanenberg^{9

13}, Bertram Opalka², Ulrich Dührsen², Hans Christian Reinhardt², Ulrich Guenther¹⁴, Nikolas von Bubnoff³, Cyrus Khandanpour^{1

2

3}

Affiliations

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.

PMID: 37423893
DOI: 10.1111/bjh.18939

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.

Keywords: AML; GFI1; metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Epigenesis, Genetic
Humans
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Mice
Myeloid-Lymphoid Leukemia Protein / genetics
Oncogene Proteins, Fusion / metabolism
Prognosis
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Transcription Factors
Myeloid-Lymphoid Leukemia Protein
Oncogene Proteins, Fusion
GFI1 protein, human
DNA-Binding Proteins