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

DNA修复 生物 奥拉帕尼 癌症研究 DNA损伤 髓系白血病 合成致死 替莫唑胺 移植 同源重组 DNA 遗传学 分子生物学 聚ADP核糖聚合酶 医学 外科 胶质母细胞瘤 聚合酶
作者
Daria Frank,Pradeep Kumar Patnana,Jan Vorwerk,Lianghao Mao,Lavanya Mokada Gopal,Noelle Jung,Thorben Hennig,Leo Ruhnke,J. Frenz,Maithreyan Kuppusamy,Robert Autry,Lanying Wei,Kaiyan Sun,Helal Mohammed Mohammed Ahmed,Axel Künstner,Hauke Busch,Heiko Müller,Stephan Hütter,Gregor Hoermann,Longlong Liu,Xiaoqing 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,Desireé 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 S. Wang,Shannon K. McWeeney,Jeffrey W. Tyner,Friedrich Stölzel,Matthias Mann,Ashok Kumar Jayavelu,Cyrus Khandanpour
出处
期刊:Blood [American Society of Hematology]
卷期号:142 (25): 2175-2191 被引量:3
标识
DOI:10.1182/blood.2022015752
摘要

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.
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