N6-methyladenine DNA Modification in Glioblastoma.

Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N6-methyladenine (N6-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N6-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N6-mA levels were dynamically regulated by the DNA demethylase ALKBH1, depletion of which led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility. Targeting the N6-mA regulator ALKBH1 in patient-derived human glioblastoma models inhibited tumor cell proliferation and extended the survival of tumor-bearing mice, supporting this novel DNA modification as a potential therapeutic target for glioblastoma. Collectively, our results uncover a novel epigenetic node in cancer through the DNA modification N6-mA.

Cytogenetic Characterization of Myeloid Neoplasms with t(2;3)(p13-25;q25-29): An Analysis of 60 Cases.

Chromosomal translocations involving the short arm of chromosome 2 (p13-25) and the distal part of the long arm of chromosome 3 (q25-29) are rare and still poorly studied to date. These abnormalities are common in myeloid neoplasms and are associated with a poor prognosis. Chromosomal abnormalities within the involved range of bands may contribute to the ectopic expression or formation of fusion genes involving the EVI1 gene, but the exact mechanism by which EVI1 affects leukemogenesis remains unclear. Herein, we report an analysis of 60 patient cases presenting various myeloid malignancies with t(2;3)(p13-25;q25-29) compiled from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. In these studies, this translocation has been reported as a sole abnormality or within the context of a complex karyotype. Among the analysis in which molecular cytogenetic analysis was performed in order to assess the involvement of the EVI1 (ecotropic virus integration site 1 proton homolog) locus (n=19), 16 (84%) confirmed its rearrangement. In 37% of studies, the t(2;3) was seen as a sole abnormality (n=22). The t(2;3) was secondary in 11% of cases (n=4), and in 63% of the cases the t(2;3) had additional chromosomal abnormalities (n=38). Monosomy 7, deletion of the 5q arm, and translocations involving (9;22) were most common abnormalities in order of prevalence, occurring in 29% (n=11), 26% (n=10), and 13% (n=5) of case studies, respectively. These observations in the results of the literature on t(2;3), an anomaly not otherwise molecularly characterized, adds to the discussion of this translocation's approximate incidence in myeloid disease, and specifically in acute myeloid leukemia (AML). The data highlights its nonrandom nature and suggests that it is a part of the myeloid spectrum of disorders. Considering the severe clinical outcome associated with this translocation, this data provides information about a cytogenetic biomarker as well as an understanding of the significance of this set of chromosomal anomalies in the development of myeloid disease.