Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia.

Abstract

Notch is needed for T-cell development and is a common oncogenic driver in T-cell acute lymphoblastic leukemia. The protooncogene c-Myc (Myc) is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates Myc is unknown. Here, we identify a distal enhancer located >1 Mb 3' of human and murine Myc that binds Notch transcription complexes and physically interacts with the Myc proximal promoter. The Notch1 binding element in this region activates reporter genes in a Notch-dependent, cell-context-specific fashion that requires a conserved Notch complex binding site. Acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer (a region spanning >600 kb) that correlate with Myc expression. This broad Notch-influenced region comprises an enhancer region containing multiple domains, recognizable as discrete H3K27 acetylation peaks. Leukemia cells selected for resistance to Notch inhibitors express Myc despite epigenetic silencing of enhancer domains near the Notch transcription complex binding sites. Notch-independent expression of Myc in resistant cells is highly sensitive to inhibitors of bromodomain containing 4 (Brd4), a change in drug sensitivity that is accompanied by preferential association of the Myc promoter with more 3' enhancer domains that are strongly dependent on Brd4 for function. These findings indicate that altered long-range enhancer activity can mediate resistance to targeted therapies and provide a mechanistic rationale for combined targeting of Notch and Brd4 in leukemia.

• Authors: Yumi Yashiro-Ohtani, Hongfang Wang, Chongzhi Zang, Kelly L Arnett, Will Bailis, Yugong Ho, Birgit Knoechel, Claudia Lanauze, Lumena Louis, Katherine S Forsyth, Sujun Chen, Yoonjie Chung, Jonathan Schug, Gerd A Blobel, Stephen A Liebhaber, Bradley E Bernstein, Stephen C Blacklow, Xiaole Shirley Liu, Jon C Aster, Warren S Pear
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 46 Pg. E4946-53 (Nov 18 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25369933 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BRD4 protein, human
• Brd4 protein, mouse
• Cell Cycle Proteins
• Histones
• Immunoglobulin J Recombination Signal Sequence-Binding Protein
• NOTCH1 protein, human
• Neoplasm Proteins
• Notch1 protein, mouse
• Nuclear Proteins
• RBPJ protein, human
• Rbpj protein, mouse
• Receptor, Notch1
• Transcription Factors

Topics

• Animals
• Base Sequence
• Cell Cycle Proteins
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Enhancer Elements, Genetic (genetics)
• Gene Expression Regulation, Leukemic (genetics)
• Genes, Reporter
• Genes, myc
• Genome-Wide Association Study
• Histones (metabolism)
• Humans
• Immunoglobulin J Recombination Signal Sequence-Binding Protein (metabolism)
• Models, Molecular
• Molecular Sequence Data
• Neoplasm Proteins (genetics, metabolism)
• Nuclear Proteins (antagonists & inhibitors)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Conformation
• Receptor, Notch1 (antagonists & inhibitors, metabolism)
• Sequence Alignment
• Sequence Homology, Nucleic Acid
• Transcription Factors (antagonists & inhibitors)
• Transcription, Genetic