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

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

Frank, Daria; Patnana, Pradeep Kumar; Vorwerk, Jan; Mao, Lianghao; Gopal, Lavanya Mokada; Jung, Noelle; Hennig, Thorben; Ruhnke, Leo; Frenz, Joris Maximillian; Kuppusamy, Maithreyan; Autry, Robert; Wei, Lanying; Sun, Kaiyan; Mohammed Ahmed, Helal Mohammed; Künstner, Axel; Busch, Hauke; Müller, Heiko; Hutter, Stephan; Hoermann, Gregor; Liu, Longlong; Xie, Xiaoqing; Al-Matary, Yahya; Nimmagadda, Subbaiah Chary; Cano, Fiorella Charles; Heuser, Michael; Thol, Felicitas; Göhring, Gudrun; Steinemann,...     »

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.      «

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 associat...     »