Drugging Chromatin in Cancer: Recent Advances and Novel Approaches

Abstract

Chromatin regulatory mechanisms play a major role in the control of gene expression programs during normal development and are disrupted in specific disease states, particularly in cancer. Important mediators of chromatin regulatory processes can broadly be classified into writers, erasers, and readers of covalent chromatin modifications that modulate eukaryotic gene transcription and maintain the integrity of the genome. The reversibility and disease-specific nature of these chromatin states make these regulators attractive therapeutic targets. As such, there is an ever-increasing number of candidate therapies aimed at targeting cancer-associated chromatin states that are in various stages of preclinical and clinical development. In this review, we discuss recent advances that have been made in the rational therapeutic targeting of chromatin regulatory mechanisms and highlight certain cancers where there is a specific rationale to assess these therapeutic approaches.

Epigenetics of hematopoiesis and hematological malignancies

“…ELL was the first MLL translocation partner for which a molecular function was demonstrated. Based on this seminal discovery, it was proposed >20 years ago that the misregulation of transcriptional elongation by RNA Pol II could play a central role in leukemic pathogenesis, a model that is now driving the clinical approaches for the treatment of leukemia associated with MLL translocations (Cai et al 2015). Purification of some of the most common MLL translocation partners led to the identification of the super elongation complex (SEC) that includes ELL; another previously known transcription elongation factor, P-TEFb; and additional MLL translocation partners AFF1, AFF4, ENL, and AF9 ( Fig.…”

“…Genetic deletion of Dot1l or pharmacological inhibition of its methyltransferase activity renders MLL chimeras unable to activate the malignant transcriptional program in mouse models (Okada et al 2005;Krivtsov et al 2008;Chang et al 2010;Bernt et al 2011;Nguyen et al 2011;Deshpande et al 2013). Consequently, a selective DOT1L small molecule inhibitor compound, EPZ-5676, has been under investigation for the treatment of MLL-rearranged leukemia (Cai et al 2015). In addition to translocations, partial tandem duplications (PTDs) of MLL have been observed in leukemia with a normal karyotype and linked to an unfavorable prognosis after treatment (Caligiuri et al , 1998Schichman et al 1994).…”

“…In contrast to genetic aberrations, epigenetic alterations are generally reversible and thus may have a more therapeutic value from a clinical standpoint. Indeed, inhibitors targeting chromatin-modifying enzymes are being used in clinical trials (Cai et al 2015;Brien et al 2016). In this review, we discuss our current understanding of how epigenetic regulators function in normal hematopoiesis and highlight the consequences of mutations in the DNA and histone lysine methylation machineries in hematological malignancies.…”

Jmjd2/Kdm4 demethylases are required for expression ofIl3raand survival of acute myeloid leukemia cells

“…Mechanistic insight into the underlying molecular basis of leukemogenesis driven by MLL1 fusions has expanded significantly within recent years (Cai et al 2015;Chen and Armstrong 2015). Wild-type MLL1 is a histone methyltransferase with specificity toward H3K4 and is required for the transcription of 1.8% of mammalian genes, including members of the homeobox (HOX) gene cluster (Rao and Dou 2015).…”

The oncogenic membrane protein LMP1 sequesters TRAF3 in B-cell lymphoma cells to produce functional TRAF3 deficiency

“…In addition to epigenetic alterations, abnormal cellular localization and expression of specific proteins can make important contributions. [66][67][68] The manner of protein alteration investigated here, sequestration by a viral tumorassociated protein, is a new mechanism to consider in examining pathogenic changes found in malignancies.…”