Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263239 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2016.12.054 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia.
Cell Rep
January 2017
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK. Electronic address:
Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body.
View Article and Find Full Text PDFMolecular cytogenetics in childhood acute lymphoblastic leukemia: a hospital-based observational study.
Clin Med Insights Oncol
April 2015
Department of Paediatrics, Government Medical College, Jammu, Jammu and Kashmir, India.
Objective: This study was conducted to determine the frequency of chromosomal aberrations in children aged <19 years with newly diagnosed acute lymphoblastic leukemia (ALL), attending/admitted in the Department of Pediatrics and Radiotherapy, Government Medical College, Jammu. Furthermore, we aimed to study the correlation between the cytogenetic molecular abnormalities and the immediate clinical outcome (induction of remission).
Materials And Methods: This was a prospective study conducted over a period of 2 years (May 2011 to May 2013) in a tertiary care hospital in India.
Down-regulation of homeobox genes MEIS1 and HOXA in MLL-rearranged acute leukemia impairs engraftment and reduces proliferation.
Proc Natl Acad Sci U S A
May 2011
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Article Synopsis
- Rearrangements of the MLL gene lead to the formation of fusion proteins that act as powerful oncogenes in acute infant and therapy-related leukemias.
- Key genes MEIS1, HOXA7, HOXA9, and HOXA10, which are often upregulated in these leukemias, were individually knocked down in a human precursor B-cell leukemia model (RS4;11) expressing MLL-AF4.
- The mutant cells showed impaired engraftment and reduced proliferation compared to control cells, signaling that all four genes are crucial for the growth and expansion of MLL-AF4 associated leukemic cells in vivo.
Novel cryptic chromosomal rearrangements in childhood acute lymphoblastic leukemia detected by multiple color fluorescent in situ hybridization.
Haematologica
September 2005
Center for Medical Genetics, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
Background And Objectives: It is often difficult to obtain good karyotypes of cells from children with acute lymphoblastic leukemia (ALL) because of poor morphology and spreading. Detailed karyotyping can be further hampered by the presence of multiple rearrangements. Our objective was to search for cryptic rearrangements in childhood ALL.
View Article and Find Full Text PDFValidation of a multiplex RT-PCR assay for screening significant oncogene fusion transcripts in children with acute lymphoblastic leukaemia.
Singapore Med J
October 2003
Paediatric Haematology-Oncology Unit, University of Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia.
In childhood acute lymphoblastic leukaemia (ALL), cytogenetics play an important role in diagnosis, allocation of treatment and prognosis. Conventional cytogenetic analysis, involving mainly karyotyping in our experience, has not been successful in a large proportion of cases due to inadequate metaphase spreads and poor chromosome morphology. Our aim is to develop a highly sensitive and specific method to screen simultaneously for the four most frequent fusion transcripts resulting from specific chromosomal translocations, namely, both the CML- and ALLtype BCR-ABL transcripts of t(9;22), E2A-PBX1 transcript of t(1;19), the MLL-AF4 transcript of t(4;11) and TEL-AML1 (also termed ETV6-CBFA2) of the cryptic t(12;21).
View Article and Find Full Text PDF