2. Academic Validation
  3. Germline variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy

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

  • Blood. 2023 Sep 26:blood.2022015752. doi: 10.1182/blood.2022015752.
Daria Frank 1,  Pradeep Kumar Patnana 2,  Jan Vorwerk 1,  Lianghao Mao 3,  Lavanya Mokada Gopal 2,  Noelle Jung 2,  Thorben Hennig 3,  Leo Ruhnke 4,  Joris Maximillian Frenz 2,  Maithreyan Kuppusamy 3,  Robert J Autry 5,  Lanying Wei 2,  Kaiyan Sun 1,  Helal Ahmed 6,  Axel Künstner 7,  Hauke Busch 8,  Heiko Müller 9,  Stephan Hutter 9,  Gregor Hoermann 9,  Longlong Liu 10,  Xiaoqing Xie 11,  Yahya Al-Matary 12,  Subbaiah Chary Nimmagadda 13,  Fiorella Charles Cano 14,  Michael Heuser 14,  Felicitas R Thol 15,  Gudrun Göhring 14,  Doris Steinemann 14,  Jürgen Thomale 16,  Theo Leitner 6,  Anja Fischer 17,  Roland Rad 17,  Christoph Röllig 18,  Heidi Altmann 19,  Desiree Kunadt 19,  Wolfgang E Berdel 20,  Jana Hüve 21,  Felix Neumann 22,  Jürgen Klingauf 22,  Virginie Calderon 22,  Bertram Opalka 23,  Ulrich Dührsen 24,  Frank Rosenbauer 24,  Martin Dugas 23,  Julian Varghese 24,  H Christian H Reinhardt 22,  Nikolas von Bubnoff 22,  Tarik Möröy 23,  Georg Lenz 25,  Aarif M N Batcha 8,  Marianna Giorgi 23,  Murugan Selvam 25,  Eunice S Wang 25,  Shannon K McWeeney 26,  Jeffrey W Tyner 27,  Friedrich Stölzel 25,  Matthias Mann 23,  Ashok Kumar Jayavelu 25,  Cyrus Khandanpour 25
Affiliations

Affiliations

  • 1 University Hospital Muenster, Muenster, Germany.
  • 2 University Münster, Germany.
  • 3 German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 4 Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany, Dresden, Germany.
  • 5 St. Jude Children's Research Hospital, Heidelberg, Tennessee, Germany.
  • 6 University Hospital of Schleswig-Holstein Campus Lübeck and University of Lübeck, Luebeck, Germany.
  • 7 University of Lübeck, Lübeck, Germany.
  • 8 Medical Systems Biology Group, Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck and Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany, Germany.
  • 9 MLL Munich Leukemia Laboratory, Munich, Germany.
  • 10 Guangzhou Medical University, Guangzhou, China.
  • 11 University Hospital Münster, Münster, Germany.
  • 12 University Hospital Essen.
  • 13 University Hospital Luebeck, Luebeck, Germany.
  • 14 German Cancer Consortium (DKTK), Partner Site Munich, Germany.
  • 15 Hannover Medical School, Hannover, Germany.
  • 16 University Hospital Essen, Essen, Germany.
  • 17 Technical University of Munich, München, Germany.
  • 18 Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany, Dresden, Germany.
  • 19 Department of Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany, Dresden, Germany.
  • 20 Universitaetsklinikum Muenster, Muenster, Germany.
  • 21 University of Münster, Münster, Germany.
  • 22 Institut de recherches cliniques de Montréal, Canada.
  • 23 Max-Planck-Institute of Biochemistry Munich, Germany.
  • 24 University Hospital of Schleswig-Holstein, Germany.
  • 25 University Hospital of Muenster, Germany.
  • 26 Oregon Health & Science University, Portland, Oregon, United States.
  • 27 Oregon Health & Science University School of Medicine, Portland, Oregon, United States.
PMID: 37756525 DOI: 10.1182/blood.2022015752
Abstract

Growth Factor Independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of haematopoiesis. GFI1-36N is a germline 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 10-15% among patients with acute myeloid leukemia (AML) and 5-7% among healthy Caucasians and promotes the development of this disease. Using a multi-omics 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-directed (HR) 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 illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a PARP1 Inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in non-malignant GFI1-36S or GFI1-36N cells. In addition, mice transplanted with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice transplanted 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 AML patients carrying the GFI1-36N variant.

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