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

Frank D; Patnana PK; Vorwerk J; Mao L; Mokada Gopal L; Jung N; Hennig T; Ruhnke L; Frenz JM; Kuppusamy M; Autry RJ; Wei L; Sun K; Ahmed H; Künstner A; Busch H; Müller H; Hutter S; Hoermann G; Liu L; Xie X; Al-Matary Y; Nimmagadda SC; Charles Cano F; Heuser M; Thol FR; Göhring G; Steinemann D; Thomale J; Leitner T; Fischer A; Rad R; Röllig C; Altmann H; Kunadt D; Berdel WE; Hüve J; Neumann F; Klingauf J; Calderon V; Opalka B; Dührsen U; Rosenbauer F; Dugas M; Varghese J; Reinhardt HCH; von Bubnoff N; Möröy T; Lenz G; Batcha AMN; Giorgi M; Selvam M; Wang ES; McWeeney SK; Tyner JW; Stölzel F; Mann M; Jayavelu AK; Khandanpour C

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.