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• W2964166353 abstract "Somatic mutations of the CUT-like homeobox 1 (CUX1) gene (CUX1MT) can be found in myeloid neoplasms (MNs), in particular, in myelodysplastic syndromes (MDSs). The CUX1 locus is also deleted in 3 of 4 MN cases with -7/del(7q). A cohort of 1480 MN patients was used to characterize clinical features and clonal hierarchy associated with CUX1MT and CUX1 deletions (CUX1DEL) and to analyze their functional consequences in vitro. CUX1MT were present in 4% of chronic MNs. CUX1DEL were preferentially found in advanced cases (6%). Most MDS and acute myeloid leukemia (AML) patients with -7/del(7q) and up to 15% of MDS patients and 5% of AML patients diploid for the CUX1 locus exhibited downmodulated CUX1 expression. In 75% of mutant cases, CUX1MT were heterozygous, whereas microdeletions and homozygous and compound-heterozygous mutations were less common. CUXMT/DEL were associated with worse survival compared with CUX1WT Within the clonal hierarchy, 1 of 3 CUX1MT served as founder events often followed by secondary BCOR and ASXL1 subclonal hits, whereas TET2 was the most common ancestral lesion, followed by subclonal CUX1MT Comet assay of patients' bone marrow progenitor cells and leukemic cell lines performed in various experimental conditions revealed that frameshift mutations, hemizygous deletions, or experimental CUX1 knockdown decrease the repair of oxidized bases. These functional findings may explain why samples with either CUX1MT or low CUX1 expression coincided with significantly higher numbers of somatic hits by whole-exome sequencing. Our findings implicate the DNA repair dysfunction resulting from CUX1 lesions in the pathogenesis of MNs, in which they lead to a mutator phenotype." @default.
• W2964166353 created "2019-07-30" @default.
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• W2964166353 date "2019-07-18" @default.
• W2964166353 modified "2023-09-30" @default.
• W2964166353 title "Distinct clinical and biological implications of CUX1 in myeloid neoplasms" @default.
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• W2964166353 doi "https://doi.org/10.1182/bloodadvances.2018028423" @default.
• W2964166353 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6650742" @default.
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