Identification of novel Nrf2/Keap1 pathway mutations in pediatric acute lymphoblastic leukemia

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dc.authoridUNAL, Mehmet Altay/0000-0001-8607-5043
dc.contributor.authorAkin-Bali, Dilara Fatma
dc.contributor.authorAktas, Sedef Hande
dc.contributor.authorUnal, Mehmet Altay
dc.contributor.authorKankilic, Teoman
dc.date.accessioned2024-11-07T13:32:14Z
dc.date.available2024-11-07T13:32:14Z
dc.date.issued2020
dc.departmentNiğde Ömer Halisdemir Üniversitesi
dc.description.abstractAcute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells, characterized by a wide range of biological and clinical heterogeneity. Oxidative stress is a common problem observed in carcinogenesis and it is involved in developing treatment resistance. Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor is the main regulator of antioxidant responses. The levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nrf2 and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Recently, many studies have shown that most of the genes in the Nrf2/Keap1/nuclear factor kappa-B (NF-kappa B)/phosphotyrosine-independent ligand for the Lck SH2 domain Of 62 KDa (p62) pathway show abnormally high mutational variations in cancer. However, variations in the Nrf2/Keap1/NF-kappa B1/p62 pathway in pediatric ALL have not been thoroughly investigated, yet. Thirty children, who were diagnosed with pediatirc ALL were included in the study. The Nrf2/Keap1/NF-kappa B1/p62 pathway variants were analyzed by DNA sequencing analysis. The PolyPhen-2 program was used for identifying pathogenic mutations. Our study examined the molecular dynamics (MD) perspectives of the effect of A159T and E121K mutations on protein stability for the first time in the literature by using the GROMACS45 software package utilizing the OPSLAA force field. Of the detected 17 nucleotide changes, 6 were novel. The study predicted the potential pathological effect of two mutations p. A159T and p.E121K in the Keap1 gene. The MD perspectives revealed that the E121K mutant's observed structural behavior accounted for the key role of His-129 and E121K, where E121K exhibited much higher drift compared to His-129. For a future perspective, it would be meaningful to study the protein-small molecule interactions of the Keap1 protein to elaborate on the drug effects in patients carrying these mutations.
dc.identifier.doi10.1080/08880018.2019.1682090
dc.identifier.endpage75
dc.identifier.issn0888-0018
dc.identifier.issn1521-0669
dc.identifier.issue1
dc.identifier.pmid31661353
dc.identifier.scopus2-s2.0-85074686722
dc.identifier.scopusqualityQ3
dc.identifier.startpage58
dc.identifier.urihttps://doi.org/10.1080/08880018.2019.1682090
dc.identifier.urihttps://hdl.handle.net/11480/15299
dc.identifier.volume37
dc.identifier.wosWOS:000493140600001
dc.identifier.wosqualityQ4
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherTaylor & Francis Inc
dc.relation.ispartofPediatric Hematology and Oncology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_20241106
dc.subjectMolecular dynamics
dc.subjectmutation
dc.subjectNF-kappa B1
dc.subjectp105
dc.subjectNrf2
dc.subjectKeap1 pathway
dc.subjectpediatric leukemia
dc.titleIdentification of novel Nrf2/Keap1 pathway mutations in pediatric acute lymphoblastic leukemia
dc.typeArticle

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