The TP53 Pro72Arg SNP in <i>de novo</i> acute myeloid leukaemia – results of two cohort studies involving 215 patients and 3759 controls

Schulz, E.; Lind, Karin; Renner, Wilfried; Petersen, Britt‐Sabina; Quehenberger, Franz; Dill, Claudia; Hofer, Sybille; Lal, Ridhima; Höefler, Gerald; Schlenke, Peter; Ehninger, Gerhard; Schetelig, Johannes; Middeke, Jan Moritz; Stölzel, Friedrich; Sill, Heinz

doi:10.1111/bjh.14527

Cited by 3 publications

(1 citation statement)

References 10 publications

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“…There were four hospital-based studies and 14 population-based studies. The characteristics of the studies included are shown in (Table 1) [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]. A total of 2337 cases and 9494 controls were investigated.…”

Section: Characteristics Of the Included Studiesmentioning

confidence: 99%

The Relationship Between Leukemia and TP53 Gene Codon Arg72Pro Polymorphism: Analysis in a Multi-Ethnic Population

et al. 2020

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Aim: Many studies have analyzed the relationship between Arg72Pro polymorphism of TP53 and leukemia; nevertheless, the findings continue to be indeterminate. We, therefore, performed an updated meta-analysis in multi-ethnic groups using specialized software for genome-wide association studies meta-analysis. Materials & methods: PubMed, EMBASE and Google Scholar were searched up to October 2018. An odds ratio (OR) with the corresponding 95% CI was used to evaluate the strength in the association. Results: This meta-analysis included 16 studies with 2337 cases and 9494 controls. In the overall population, significant relationship between Arg72Pro polymorphism of TP53 and leukemia susceptibility was found in two genetic models (recessive model: OR = 1.276, 95% CI = 1.102–1.476; p = 0.01; overdominant model: OR = 0.891, 95% CI = 0.802–0.988; p = 0.03). In stratified studies with ethnicity, a significant association was found in five ethnic groups, including Chinese, Americans, Africans, Japanese and Indians. Conclusion: We demonstrated that an association exist between leukemia risk and TP53 gene codon Arg72Pro polymorphism in the recessive and overdominant genetic models. Also, our findings show that the TP53 Arg72Pro polymorphism may influence leukemia development in different populations.

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Section: Characteristics Of the Included Studiesmentioning

confidence: 99%

The Relationship Between Leukemia and TP53 Gene Codon Arg72Pro Polymorphism: Analysis in a Multi-Ethnic Population

et al. 2020

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

Frank,

Patnana,

Vorwerk

et al. 2023

Blood

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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.

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The TP53 Pro72Arg SNP in de novo acute myeloid leukemia

Schulz

Sill

2017

Haematologica

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The TP53 Pro72Arg SNP in de novo acute myeloid leukaemia – results of two cohort studies involving 215 patients and 3759 controls

Cited by 3 publications

References 10 publications

The Relationship Between Leukemia and TP53 Gene Codon Arg72Pro Polymorphism: Analysis in a Multi-Ethnic Population

The Relationship Between Leukemia and TP53 Gene Codon Arg72Pro Polymorphism: Analysis in a Multi-Ethnic Population

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

The TP53 Pro72Arg SNP in de novo acute myeloid leukemia

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