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Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy. 2023
Daria Frank, and
Pradeep Kumar Patnana, and
Jan Vorwerk, and
Lianghao Mao, and
Lavanya Mokada Gopal, and
Noelle Jung, and
Thorben Hennig, and
Leo Ruhnke, and
Joris Maximillian Frenz, and
Maithreyan Kuppusamy, and
Robert Autry, and
Lanying Wei, and
Kaiyan Sun, and
Helal Mohammed Mohammed Ahmed, and
Axel Künstner, and
Hauke Busch, and
Heiko Müller, and
Stephan Hutter, and
Gregor Hoermann, and
Longlong Liu, and
Xiaoqing Xie, and
Yahya Al-Matary, and
Subbaiah Chary Nimmagadda, and
Fiorella Charles Cano, and
Michael Heuser, and
Felicitas Thol, and
Gudrun Göhring, and
Doris Steinemann, and
Jürgen Thomale, and
Theo Leitner, and
Anja Fischer, and
Roland Rad, and
Christoph Röllig, and
Heidi Altmann, and
Desiree Kunadt, and
Wolfgang E Berdel, and
Jana Hüve, and
Felix Neumann, and
Jürgen Klingauf, and
Virginie Calderon, and
Bertram Opalka, and
Ulrich Dührsen, and
Frank Rosenbauer, and
Martin Dugas, and
Julian Varghese, and
Hans Christian Reinhardt, and
Nikolas von Bubnoff, and
Tarik Möröy, and
Georg Lenz, and
Aarif M N Batcha, and
Marianna Giorgi, and
Murugan Selvam, and
Eunice Wang, and
Shannon K McWeeney, and
Jeffrey W Tyner, and
Friedrich Stölzel, and
Matthias Mann, and
Ashok Kumar Jayavelu, and
Cyrus Khandanpour
Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.
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.
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