Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Daria Frank - , University Hospital Münster (Author)
  • Pradeep Kumar Patnana - , University Hospital Münster (Author)
  • Jan Vorwerk - , University Hospital Münster (Author)
  • Lianghao Mao - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Lavanya Mokada Gopal - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Noelle Jung - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Thorben Hennig - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Leo Ruhnke - , University Hospital Carl Gustav Carus Dresden, Department of internal Medicine I (Author)
  • Joris Maximillian Frenz - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Maithreyan Kuppusamy - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Robert Autry - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Lanying Wei - , University Hospital Münster (Author)
  • Kaiyan Sun - , University Hospital Münster (Author)
  • Helal Mohammed Mohammed Ahmed - , University Hospital Münster (Author)
  • Axel Künstner - , University of Music Lübeck (Author)
  • Hauke Busch - , University of Music Lübeck (Author)
  • Heiko Müller - , Munich Leukemia Laboratory (Author)
  • Stephan Hutter - , Munich Leukemia Laboratory (Author)
  • Gregor Hoermann - , Munich Leukemia Laboratory (Author)
  • Longlong Liu - , University Hospital Münster (Author)
  • Xiaoqing Xie - , University Hospital Münster (Author)
  • Yahya Al-Matary - , LVR University Hospital Essen (Author)
  • Subbaiah Chary Nimmagadda - , University Hospital Münster (Author)
  • Fiorella Charles Cano - , Hannover Medical School (MHH) (Author)
  • Michael Heuser - , Hannover Medical School (MHH) (Author)
  • Felicitas Thol - , Hannover Medical School (MHH) (Author)
  • Gudrun Göhring - , Hannover Medical School (MHH) (Author)
  • Doris Steinemann - , Hannover Medical School (MHH) (Author)
  • Jürgen Thomale - , LVR University Hospital Essen (Author)
  • Theo Leitner - , University of Music Lübeck (Author)
  • Anja Fischer - , Institute of Molecular Oncology and Functional Genomics (Author)
  • Roland Rad - , Institute of Molecular Oncology and Functional Genomics (Author)
  • Christoph Röllig - , Department of internal Medicine I, Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Heidi Altmann - , Department of internal Medicine I (Author)
  • Desiree Kunadt - , Department of internal Medicine I (Author)
  • Wolfgang E Berdel - , University Hospital Münster (Author)
  • Jana Hüve - , University Hospital Münster (Author)
  • Felix Neumann - , University Hospital Münster (Author)
  • Jürgen Klingauf - , University Hospital Münster (Author)
  • Virginie Calderon - , Bioinformatic Core Facility (Author)
  • Bertram Opalka - , LVR University Hospital Essen (Author)
  • Ulrich Dührsen - , LVR University Hospital Essen (Author)
  • Frank Rosenbauer - , University Hospital Münster (Author)
  • Martin Dugas - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Julian Varghese - , University Hospital Münster (Author)
  • Hans Christian Reinhardt - , LVR University Hospital Essen (Author)
  • Nikolas von Bubnoff - , University of Music Lübeck (Author)
  • Tarik Möröy - , Institut de Recherches Cliniques de Montréal (IRCM) (Author)
  • Georg Lenz - , University Hospital Münster (Author)
  • Aarif M N Batcha - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Marianna Giorgi - , Jacobs School of Medicine and Biomedical Sciences (Author)
  • Murugan Selvam - , Jacobs School of Medicine and Biomedical Sciences (Author)
  • Eunice Wang - , Jacobs School of Medicine and Biomedical Sciences (Author)
  • Shannon K McWeeney - , Oregon Health and Science University (Author)
  • Jeffrey W Tyner - , Oregon Health and Science University (Author)
  • Friedrich Stölzel - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck, University Hospital Schleswig-Holstein Campus Kiel, Christian Albrecht University Kiel (Author)
  • Matthias Mann - , Max Planck Institute of Biochemistry (Author)
  • Ashok Kumar Jayavelu - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Cyrus Khandanpour - , University Hospital Münster (Author)

Abstract

Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

Details

Original languageEnglish
Pages (from-to)2175-2191
Number of pages17
JournalBlood
Volume142
Issue number25
Publication statusPublished - 21 Dec 2023
Peer-reviewedYes

External IDs

PubMedCentral PMC10733838
Scopus 85175819248

Keywords

Sustainable Development Goals

Keywords

  • Humans, Mice, Animals, DNA-Binding Proteins/genetics, Temozolomide, Leukemia, Myeloid, Acute/drug therapy, DNA Damage, DNA Repair, Germ Cells/metabolism, DNA, Transcription Factors/genetics