Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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.
Details
Original language | English |
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Pages (from-to) | 2175-2191 |
Number of pages | 17 |
Journal | Blood |
Volume | 142 |
Issue number | 25 |
Publication status | Published - 21 Dec 2023 |
Peer-reviewed | Yes |
External IDs
PubMedCentral | PMC10733838 |
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Scopus | 85175819248 |
Keywords
Sustainable Development Goals
Keywords
- Humans, Mice, Animals, DNA-Binding Proteins/genetics, Temozolomide, Leukemia, Myeloid, Acute/drug therapy, DNA Damage, DNA Repair, Germ Cells/metabolism, DNA, Transcription Factors/genetics