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

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 language	English
Journal	British Journal of Haematology
Volume	202
Issue number	5
Pages (from-to)	1033-1048
Number of pages	16
ISSN	0007-1048
DOIs	https://doi.org/10.1111/bjh.18939
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Patnana, P. K., Liu, L., Frank, D., Nimmagadda, SC., 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., ... Khandanpour, C. (2023). Dose-dependent expression of GFI1 alters metabolism in the haematopoietic progenitors and MLL::AF9-induced leukaemic cells. British Journal of Haematology, 202(5), 1033-1048. https://doi.org/10.1111/bjh.18939

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.",

year = "2023",

month = sep,

doi = "10.1111/bjh.18939",

language = "English",

volume = "202",

pages = "1033--1048",

journal = "British Journal of Haematology",

issn = "0007-1048",

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Patnana, PK, Liu, L, Frank, D, Nimmagadda, SC, Behrens, M, Ahmed, H, Xie, X, Liebmann, M, Wei, L, Gerdemann, A, Thivakaran, A, Humpf, HU, Klotz, L, Dugas, M, Varghese, J, Trajkovic-Arsic, M, Siveke, JT, Hanenberg, H, Opalka, B, Dührsen, U, Reinhardt, HC, Guenther, U, von Bubnoff, N & Khandanpour, C 2023, 'Dose-dependent expression of GFI1 alters metabolism in the haematopoietic progenitors and MLL::AF9-induced leukaemic cells', British Journal of Haematology, vol. 202, no. 5, pp. 1033-1048. https://doi.org/10.1111/bjh.18939

TY - JOUR

T1 - Dose-dependent expression of GFI1 alters metabolism in the haematopoietic progenitors and MLL::AF9-induced leukaemic cells

AU - Patnana, Pradeep Kumar

AU - Liu, Longlong

AU - Frank, Daria

AU - Nimmagadda, Subbaiah Chary

AU - Behrens, Matthias

AU - Ahmed, Helal

AU - Xie, Xiaoqing

AU - Liebmann, Marie

AU - Wei, Lanying

AU - Gerdemann, Andrea

AU - Thivakaran, Aniththa

AU - Humpf, Hans Ulrich

AU - Klotz, Luisa

AU - Dugas, Martin

AU - Varghese, Julian

AU - Trajkovic-Arsic, Marija

AU - Siveke, Jens T.

AU - Hanenberg, Helmut

AU - Opalka, Bertram

AU - Dührsen, Ulrich

AU - Reinhardt, Hans Christian

AU - Guenther, Ulrich

AU - von Bubnoff, Nikolas

AU - Khandanpour, Cyrus

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85164570701&partnerID=8YFLogxK

U2 - 10.1111/bjh.18939

DO - 10.1111/bjh.18939

M3 - Journal articles

C2 - 37423893

AN - SCOPUS:85164570701

SN - 0007-1048

VL - 202

SP - 1033

EP - 1048

JO - British Journal of Haematology

JF - British Journal of Haematology

IS - 5

ER -

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

Abstract

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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