BET

Overview

The bromodomain and extraterminal (BET) proteins are a bromodomain subfamily that includes BRD2, BRD3, BRD4, and BRDT.1

  • Characterized by the presence of two tandem bromodomains (BD1 & BD2) and an extra-terminal domain2,4

The BET proteins utilize the bromodomains to interact with acetylated histone tails of chromatin to mediate downstream functions, such as histone acetylation, chromatin remodeling, and transcriptional regulation.1,3,6

  • Binding of BET proteins targets chromatin-modifying enzymes to specific sites6
  • At those sites, transcription may be either stimulated or silenced6

IMPLICATIONS IN CANCER

BET family proteins are involved in promoting aberrant oncogene expression in a variety of cancers.7-10

Overexpression and gain-of-function mutations of BET proteins can alter gene transcription, histone modification, DNA repair, and apoptosis.1

  • BET proteins serve to regulate the expression of important oncogenes, including those involved in apoptosis as well as cell cycle progression.3
  • Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes.1,11
  • Genetic rearrangements of BRD-containing proteins have been linked to the development of a number of extremely aggressive tumors.6

Small molecule inhibition of BET proteins have been investigated and demonstrate promising activity in both solid and hematologic malignancies.3

Oncogenic Expression

Acute Myeloid Leukemia

The BET family of proteins may be involved in the pathogenesis of AML, particularly in AML harboring mutations in NPM1 and MLL.12

  • Dysregulated transcription causes overexpression of critical oncogenes, including c-Myc and BCL-2.12,13

Additionally, the BET family of proteins likely promotes oncogenesis through a number of shared pathways activated in FLT3 AML, including STAT5, AKT, and ERK.9,12

  • BET inhibition has been proposed as a therapeutic option for TKI-resistant FLT3-ITD AML.12
  1. Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017;16(4):241-263.
  2. Zeng L, Zhou MM. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513(1):124-128.
  3. Wadhwa E, Nicolaides T. Bromodomain inhibitor review: bromodomain and extra-terminal family protein inhibitors as a potential new therapy in central nervous system tumors. Cureus. 2016;8(5):e620.
  4. Garcia-Gutierrez P, Mundi M, Garcia-Dominguez M. Association of bromodomain BET proteins with chromatin requires dimerization through the conserved motif B. J Cell Sci. 2012;125(Pt 15):3671-3680.
  5. Wu SY, Chiang CM. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem. 2007;282(18):13141-13145.
  6. Muller S, Filippakopoulos P, Knapp S. Bromodomains as therapeutic targets. Expert Rev Mol Med. 2011;13:e29.
  7. Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6(8):5501-5516.
  8. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.
  9. Liu S, Walker SR, Nelson EA, et al. Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2. Mol Cancer Ther. 2014;13(5):1194-1205.
  10. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108(40):16669-16674.
  11. Jung M, Gelato KA, Fernández-Montalván A, Siegel S, Haendler B. Targeting BET bromodomains for cancer treatment. Epigenomics. 2015;7(3):487-501.
  12. Abedin SM, et al. BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects. Onco Targets Ther. 2016;9:5943-5953.
  13. Dawson MA, Gudgin EJ, Horton SJ, et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia. 2014;28(2):311-320.
  14. Delmore JE, et al. BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc. Cell. 2011;146:904–917.
  15. French CA. Chapter Two - Small-Molecule Targeting of BET Proteins in Cancer. Adv Cancer Res. 2016;131:21-58.

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