Assessing acute myeloid leukemia susceptibility in rearrangement-driven patients by DNA breakage at topoisomerase II and CCCTC-binding factor/cohesin binding sites.

Atkin, Naomi D; Raimer, Heather M; Wang, Zhenjia; Zang, Chongzhi; Wang, Yuh-Hwa

Atkin, Naomi D; Raimer, Heather M; Wang, Zhenjia; Zang, Chongzhi; Wang, Yuh-Hwa.

Afiliación

Atkin ND; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Raimer HM; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Wang Z; Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Zang C; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Wang YH; Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Genes Chromosomes Cancer ; 60(12): 808-821, 2021 12.

Article en En | MEDLINE | ID: mdl-34405474

RESUMEN

An initiating DNA double strand break (DSB) event precedes the formation of cancer-driven chromosomal abnormalities, such as gene rearrangements. Therefore, measuring DNA breaks at rearrangement-participating regions can provide a unique tool to identify and characterize susceptible individuals. Here, we developed a highly sensitive and low-input DNA break mapping method, the first of its kind for patient samples. We then measured genome-wide DNA breakage in normal cells of acute myeloid leukemia (AML) patients with KMT2A (previously MLL) rearrangements, compared to that of nonfusion AML individuals, as a means to evaluate individual susceptibility to gene rearrangements. DNA breakage at the KMT2A gene region was significantly greater in fusion-driven remission individuals, as compared to nonfusion individuals. Moreover, we identified select topoisomerase II (TOP2)-sensitive and CCCTC-binding factor (CTCF)/cohesin-binding sites with preferential DNA breakage in fusion-driven patients. Importantly, measuring DSBs at these sites, in addition to the KMT2A gene region, provided greater predictive power when assessing individual break susceptibility. We also demonstrated that low-dose etoposide exposure further elevated DNA breakage at these regions in fusion-driven AML patients, but not in nonfusion patients, indicating that these sites are preferentially sensitive to TOP2 activity in fusion-driven AML patients. These results support that mapping of DSBs in patients enables discovery of novel break-prone regions and monitoring of individuals susceptible to chromosomal abnormalities, and thus cancer. This will build the foundation for early detection of cancer-susceptible individuals, as well as those preferentially susceptible to therapy-related malignancies caused by treatment with TOP2 poisons.

Asunto(s)

Factor de Unión a CCCTC/genética; ADN-Topoisomerasas de Tipo II/genética; N-Metiltransferasa de Histona-Lisina/genética; Leucemia Mieloide Aguda/genética; Proteína de la Leucemia Mieloide-Linfoide/genética; Proteínas de Unión a Poli-ADP-Ribosa/genética; Sitios de Unión/genética; Factor de Unión a CCCTC/sangre; Proteínas de Ciclo Celular/sangre; Proteínas de Ciclo Celular/genética; Proteoglicanos Tipo Condroitín Sulfato/sangre; Proteoglicanos Tipo Condroitín Sulfato/genética; Proteínas Cromosómicas no Histona/sangre; Proteínas Cromosómicas no Histona/genética; Aberraciones Cromosómicas; Roturas del ADN de Doble Cadena/efectos de los fármacos; Reparación del ADN/genética; ADN-Topoisomerasas de Tipo II/sangre; Proteínas de Unión al ADN/sangre; Proteínas de Unión al ADN/genética; Etopósido/farmacología; Femenino; Reordenamiento Génico/genética; Genoma Humano/genética; Células HeLa; N-Metiltransferasa de Histona-Lisina/sangre; Humanos; Leucemia Mieloide Aguda/sangre; Leucemia Mieloide Aguda/patología; Masculino; Proteína de la Leucemia Mieloide-Linfoide/sangre; Proteínas de Fusión Oncogénica/genética; Proteínas de Unión a Poli-ADP-Ribosa/sangre; Cohesinas

Palabras clave

CTCF; DNA fragility; acute myeloid leukemia; cohesin; topoisomerase

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / N-Metiltransferasa de Histona-Lisina / ADN-Topoisomerasas de Tipo II / Proteína de la Leucemia Mieloide-Linfoide / Proteínas de Unión a Poli-ADP-Ribosa / Factor de Unión a CCCTC Tipo de estudio: Prognostic_studies / Screening_studies Límite: Female / Humans / Male Idioma: En Revista: Genes Chromosomes Cancer Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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