A growing number of human diseases have been found to be associated with aberrant DNA methylation, including cancer. Mutations targeting genes encoding DNA methyltransferase (DNMT), TET family of DNA demethylases, and isocitrate dehydrogenase (IDH1, IDH2) that produce TET inhibitory metabolite, 2-hyoxyglutarate (2-HG), are found in more than half of acute myeloid leukemia (AML). To gain new insights into the regulation of DNA de/methylation and consequence of its alteration in cancer development, we searched for genes which are mutated in a manner that is linked with gene mutations involved in DNA de/methylation in multiple cancer types. We found that recurrent CBFB-MYH11 fusions, which result in the expression of fusion protein comprising core-binding factor β (CBFB) and myosin heavy chain 11 (MYH11) and are found in 6∼8% of AML patients, occur mutually exclusively with DNMT3A mutations. Tumors bearing CBFB-MYH11 fusion show DNA hypomethylation patterns similar to those with loss-of-function mutation of DNMT3A. Expression of CBFB-MYH11 fusion or inhibition of DNMT3A similarly impairs the methylation and expression of target genes of Runt related transcription factor 1 (RUNX1), a functional partner of CBFB. We demonstrate that RUNX1 directly interacts with DNMT3A and that CBFB-MYH11 fusion protein sequesters RUNX1 in the cytoplasm, thereby preventing RUNX1 from interacting with and recruiting DNMT3A to its target genes. Our results identify a novel regulation of DNA methylation and provide a molecular basis how CBFB-MYH11 fusion contributes to leukemogenesis.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321512 | PMC |
http://dx.doi.org/10.3389/fcell.2021.675424 | DOI Listing |
Inversion of chromosome 16 [inv(16)] is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML) and generates the fusion gene , which initiates leukemogenesis. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that is required after leukemic transformation. However, this has yet to be shown experimentally.
View Article and Find Full Text PDFPathology
November 2024
Department of Haematology, Monash Health, Clayton, Vic, Australia; Department of Diagnostic Genomics, Monash Health, Clayton, Vic, Australia; School of Clinical Sciences, Monash University, Clayton, Vic, Australia. Electronic address:
Haematological malignancies are being increasingly defined by gene rearrangements, which have traditionally been detected by karyotype, fluorescent in situ hybridisation (FISH) or reverse-transcriptase polymerase chain reaction (RT-PCR). However, these traditional methods may miss cryptic gene rearrangements and are limited by the number of gene rearrangements screened at any one time. A next-generation sequencing (NGS) RNA fusion panel is an evolving technology that can identify multiple fusion transcripts in a single molecular assay, even without prior knowledge of breakpoints or fusion partners.
View Article and Find Full Text PDFJ Mol Diagn
November 2024
Hematology Laboratory, Rennes University Hospital, Rennes, France; Inserm U1236, Rennes University, Rennes, France. Electronic address:
In Vivo
June 2024
Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, Brazil;
Background/aim: Acute myeloid leukemia (AML) is a myeloproliferative neoplasm marked by abnormal clonal expansion of hematopoietic progenitor cells, displaying karyotypic aberrations and genetic mutations as prognostic indicators. The World Health Organization (WHO) and the European LeukemiaNet guidelines categorize BCR::ABL1 p190+ AML as high risk. This study explored the identification of the increased incidence of BCR::ABL1 p190+ in our AML population.
View Article and Find Full Text PDFA distinct subset of acute myeloid leukemia (AML) is characterized by the presence of the Philadelphia chromosome (Ph+), due to reciprocal translocation t(9;22)(q34;q11.2). This chromosomal rearrangement leads to the fusion of the breakpoint cluster region (BCR) gene on chromosome 22 with the ABL1 gene on chromosome 9, generating the fusion gene.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!