Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.
In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase-binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
Marc R
MR
Mansour
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Brian J
BJ
Abraham
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Lars
L
Anders
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Alla
A
Berezovskaya
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Division of Pediatric Hematology-Oncology, Boston Children's Hospital, MA 02115, USA.
Alejandro
A
Gutierrez
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Adam D
AD
Durbin
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Julia
J
Etchin
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Lee
L
Lawton
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Division of Pediatric Hematology-Oncology, Boston Children's Hospital, MA 02115, USA.
Stephen E
SE
Sallan
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Division of Pediatric Hematology-Oncology, Boston Children's Hospital, MA 02115, USA.
Lewis B
LB
Silverman
Department of Pediatrics, Benioff Children's Hospital, University of California San Francisco, CA 94143, USA.
Mignon L
ML
Loh
Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO 80045, USA.
Stephen P
SP
Hunger
Cancer Science Institute of Singapore, National University of Singapore, and Department of Medicine, Yong Loo Lin School of Medicine, 117599, Singapore.
Takaomi
T
Sanda
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. thomas_look@dfci.harvard.edu young@wi.mit.edu.
Richard A
RA
Young
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Division of Pediatric Hematology-Oncology, Boston Children's Hospital, MA 02115, USA. thomas_look@dfci.harvard.edu young@wi.mit.edu.
A Thomas
AT
Look
D000107:Acetylation; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001665:Binding Sites; D045744:Cell Line, Tumor; D021901:DNA, Intergenic; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D054643:INDEL Mutation; D008969:Molecular Sequence Data; D009154:Mutation; D009857:Oncogenes; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D054730:Protein Interaction Domains and Motifs; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D021901:DNA, Intergenic; D006657:Histones; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C067143:TAL1 protein, human