Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.
Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.
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DOI：
10.1182/blood.2022015752
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发表时间：
2023-12-21
期刊：
影响因子：
20.3
通讯作者：
Khandanpour, Cyrus
中科院分区：
文献类型：
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作者：
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;Kunstner, Axel;Busch, Hauke;Muller, Heiko;Hutter, Stephan;Hoermann, Gregor;Liu, Longlong;Xie, Xiaoqing;Al-Matary, Yahya;Nimmagadda, Subbaiah Chary;Cano, Fiorella Charles;Heuser, Michael;Thol, Felicitas;Gohring, Gudrun;Steinemann, Doris;Thomale, Jurgen;Leitner, Theo;Fischer, Anja;Rad, Roland;Rollig, Christoph;Altmann, Heidi;Kunadt, Desiree;Berdel, Wolfgang E;Huve, Jana;Neumann, Felix;Klingauf, Jurgen;Calderon, Virginie;Opalka, Bertram;Duhrsen, Ulrich;Rosenbauer, Frank;Dugas, Martin;Varghese, Julian;Reinhardt, Hans Christian;von Bubnoff, Nikolas;Moroy, Tarik;Lenz, Georg;Batcha, Aarif M N;Giorgi, Marianna;Selvam, Murugan;Wang, Eunice;McWeeney, Shannon K;Tyner, Jeffrey W;Stolzel, Friedrich;Mann, Matthias;Jayavelu, Ashok Kumar;Khandanpour, Cyrus
GFI1-36N的存在选择性地抑制HR和MGMT介导的AML细胞DNA修复。替莫唑胺和奥拉帕利的使用允许选择性靶向GFI1-36N白血病细胞。生长因子独立1(GFI1)是一种DNA结合的转录因子，是造血的关键调控因子。GFI1-36N是一个生殖系变异，导致36位丝氨酸(S)变为天冬氨酸(N)。我们先前报道，GFI1-36N等位基因在急性髓系白血病(AML)患者中的患病率为10%~15%，在健康的高加索人中为5%~7%，并促进了这种疾病的发展。使用多组学方法，我们在这里表明，GFI1-36N的表达与小鼠和人类AML中染色体异常、突变负担和突变特征的频率增加有关，并阻碍了白血病细胞中同源重组(HR)导向的DNA修复。转录组和蛋白质组分析表明，GFI1-36N表现出与N-Myc下游调节基因1(Ndrg1)调控元件的结合受损，导致NDRG1水平下降，导致O6-甲基鸟嘌呤-DNA-甲基转移酶(MGMT)表达水平下降。通过DNA烷化药物替莫唑胺靶向MGMT，通过多聚ADP核糖聚合酶1抑制剂olaparib靶向HR，在表达GFI1-36N的人和小鼠AML样本中引起合成致死性，而在非恶性GFI1-36S或GFI1-36N细胞中作用不明显。此外，接受GFI1-36N白血病细胞移植的小鼠，与接受GFI1-36S白血病细胞移植的小鼠相比，接受替莫唑胺和奥拉帕利联合治疗的小鼠无AML存活时间显著延长。这表明，MGMT表达的减少使GFI1-36N白血病细胞特别容易受到DNA损伤的影响，从而启动化疗。我们的数据为治疗携带GFI1-36N变异的AML患者的新选择提供了关键的见解。生长因子独立1(GFI1)是一种重要的造血转录调控因子。在5-7%的高加索人中存在一种生殖系GFI1变异体GFI1-36N，但在急性髓系白血病(AML)患者中的比例高达10%-15%。Frank和他的同事描述了GFI1-36N细胞增加了突变负担和染色体畸变率，并表现出DNA修复受损。作者将O6-甲基鸟嘌呤-DNA-甲基转移酶(MGMT)确定为GFI1-36N的下游靶标。MGMT抑制剂替莫唑胺和PARP抑制剂联合使用可杀死GIF1-36N相关的AML细胞，这表明可能是治疗GFI1-36N相关AML的一种新方法。
Presence of GFI1-36N impedes HR- and MGMT-mediated DNA repair selectively in AML cells. Use of temozolomide and olaparib allows for selective targeting of GFI1-36N leukemic cells. 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 key transcriptional regulator of hematopoiesis. A germ line GFI1 variant, GFI1-36N, is present in 5-7% of Caucasians but is enriched to 10-15% in patients with acute myeloid leukemia (AML). Frank and colleagues delineate that GFI1-36N cells have increased mutational burden and chromosomal aberrations and also evince impaired DNA repair. The authors identify O6-methylguaninine-DNA-methyltransferase (MGMT) as a downstream target of GFI1-36N. Combination of the MGMT inhibitor temozolomide and a PARP inhibitor kills GIF1-36N–associated AML cells, suggesting a potential novel therapy for GFI1-36N–associated AML.