Germline variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy PMID: 37756525

ADC Targets in Oncology

2026-04-10

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

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.

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.