Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma
Mariateresa Fulciniti,
Charles Y. Lin,
Mehmet K. Samur,
Michael A. Lopez,
Irtisha Singh,
Matthew A. Lawlor,
Raphael E. Szalat,
Christopher J. Ott,
Herve’ Avet-Loiseau,
Kenneth C. Anderson,
Richard A. Young,
James E. Bradner,
Nikhil C. Munshi
Affiliations
Mariateresa Fulciniti
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Charles Y. Lin
Baylor College of Medicine, Houston, TX, USA
Mehmet K. Samur
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Michael A. Lopez
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Irtisha Singh
Baylor College of Medicine, Houston, TX, USA
Matthew A. Lawlor
Massachussets General Hospital, Harvard Medical School, Boston, MA, USA
Raphael E. Szalat
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Christopher J. Ott
Massachussets General Hospital, Harvard Medical School, Boston, MA, USA
Herve’ Avet-Loiseau
Centre Hospitalier Universitaire, Toulouse, France
Kenneth C. Anderson
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Richard A. Young
Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Massachusetts Institute of Technology, Cambridge, MA, USA
James E. Bradner
Novartis Institute for Biomedical Research, Cambridge, MA, USA
Nikhil C. Munshi
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; VA Boston Healthcare System, Boston, MA, USA; Corresponding author
Summary: The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth and/or proliferation genes and BETs disproportionately at enhancer-regulated tissue-specific genes. These two separate gene regulatory axes can be simultaneously targeted to impair the myeloma proliferative program, providing an important molecular mechanism for combination therapy. This study therefore suggests a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy. : Uncontrolled proliferation is a hallmark of tumorigenesis and is associated with perturbed transcriptomic profile. Fulciniti et al. explored the interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma, reporting the existence of two distinct regulatory axes that can be synergistically targeted to impact myeloma growth and survival. Keywords: multiple myeloma, transcription factor, transcriptional regulation, super-enhancers
