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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2175-2191
Number of pages17
JournalBlood
Volume142
Issue number25
DOIs
StatePublished - 21 Dec 2023
Externally publishedYes

Fingerprint

Dive into the research topics of 'Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy'. Together they form a unique fingerprint.

Cite this