Chromatin modifications as therapeutic targets in MLL-rearranged leukemia - PubMed (original) (raw)

Review

Chromatin modifications as therapeutic targets in MLL-rearranged leukemia

Aniruddha J Deshpande et al. Trends Immunol. 2012 Nov.

Abstract

MLL-rearranged leukemias exemplify malignancies with perturbations of the epigenetic landscape. Specific chromatin modifications that aid in the perpetuation of MLL fusion gene driven oncogenic programs are being defined, presenting novel avenues for therapeutic intervention. Proof-of-concept studies have recently been reported, using small-molecule inhibitors targeting the histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L), or the acetyl-histone binding protein bromodomain containing protein 4 (BRD4) showing potent activity against MLL-rearranged leukemias in preclinical models. It is apparent that intensive efforts will be made toward the further development of small-molecule inhibitors targeting these, and other chromatin-associated protein targets. These studies may lead to the advent of a new generation of much-needed therapeutic modalities in leukemia and other cancers.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Figures

Fig.1

Fig.1. Complexes involved in transcriptional activation in the MLL-rearranged leukemias

Of the several different complexes that are thought to be important for MLL-leukemogenesis, the Dot1l complex (a), the SEC complex (b) and the Brd4 complex (c) are depicted. Overlapping components are highlighted by enclosing with dotted rectangles. The Dot1l complex (DotCom) consists of the histone methyltransferase Dot1l and the MLL fusion partners AF10, AF9, ENL and AF17, along with components of the Wnt signaling pathway. The AEP/EAP and SEC complexes comprise of a number of unique and overlapping components and notably, several proteins in these complexes participate in fusions with MLL. The PAFc complex, which physically interacts with the N-terminal part of wild-type MLL as well as with MLL fusion genes is a multi-protein complex that consists of the core components PAF1, LEO1, CDC73, CTR9 and WDR61 (reviewed in(96)). Recently, BRD4 was shown to co-purify with some components of both the SEC as well as the PAFc complexes; however, it is yet unclear whether BRD4 is part of the MLL-AF9/PAFc/SEC multi-subunit complex or if it associates with PAFc/SEC in other complexes which are independent from the MLL-fusion protein.

Fig.2

Fig.2. Pharmacological targeting of chromatin regulatory pathways in MLL-rearranged leukemias

A: Using MLL-AF9 as an example, the cartoon depiction shows the association of the Dot1l histone methyltransferase with the AF9 part of the MLL-AF9 fusion. The Dot1l histone methyltransferase methylates histone 3 at lysine residue 79 (H3K79) using S-(5′-adenosyl)-l-methionine (SAM) as a donor. Current models suggest that aberrant recruitment of this enzyme to MLL-target loci leads to constitutive activation of MLL-target genes. The use of a SAM mimetic, eg., EPZ0004777, (lower panel) that mimics the binding of Dot1l to SAM, can potently inhibit Dot1l activity, serving as a candidate therapeutic agent targeting oncogenic H3K79 hypermethylation. B: MLL fusions such as MLL-AF9 (used as a typical example) recruit the PAFc complex through the N-terminal portion of MLL. A number of nuclear fusion partners such as AF9, ENL, and AF5q31 are a part of the SEC complex which includes the transcription elongation factor P-TEFb. Both the PAFc and the SEC complexes have been implicated in MLL-fusion mediated leukemia. Recently, it was demonstrated that the acetyl-lysine recognizing bromodomain protein BRD4 co-purifies with a number of components of the PAFc and the SEC complexes. The inhibition of acetyl lysine recognition by BRD4 using a BET family inhibitor (lower panel) was shown to preclude the targeting of the PAFc and SEC complex components to chromatin, leading to down regulation of gene expression. Targeting of acetyl-lysine recognition by BRD4 using small-molecule inhibitors (lower panel) could therefore inhibit MLL-fusion mediated transformation as described in these studies (8, 9). It must be noted however that BRD4 has not yet been identified in MLL-fusion protein complexes. Therefore, it is not clear whether the BRD4/PAFc/SEC complex and the MLL-fusion/PAFc/SEC complexes are overlapping, or control different sub-sets of an oncogenic transcriptional program (See also Box 2).

Similar articles

Cited by

References

    1. Kouzarides T. Chromatin modifications and their function. Cell. 2007 Feb 23;128(4):693–705. - PubMed
    1. Chi P, Allis CD, Wang GG. Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer. 2010 Jul;10(7):457–469. - PMC - PubMed
    1. Issa JP, Kantarjian HM, Kirkpatrick P. Azacitidine. Nat Rev Drug Discov. 2005 Apr;4(4):275–276. - PubMed
    1. Gore SD, Jones C, Kirkpatrick P. Decitabine. Nat Rev Drug Discov. 2006 Nov;5(11):891–892. - PubMed
    1. Marks PA. The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opin Investig Drugs. 2010 Sep;19(9):1049–1066. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources