Therapeutic Opportunities of Targeting Canonical and Noncanonical PcG/TrxG Functions in Acute Myeloid Leukemia.

Bernd B Zeisig,Chi Wai Eric So

doi:10.1146/annurev-genom-111120-102443

Bernd B Zeisig, Chi Wai Eric So

Open Access

https://doi.org/10.1146/annurev-genom-111120-102443

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Abstract

Transcriptional deregulation is a key driver of acute myeloid leukemia (AML), a heterogeneous blood cancer with poor survival rates. Polycomb group (PcG) and Trithorax group (TrxG) genes, originally identified in Drosophila melanogaster several decades ago as master regulators of cellular identity and epigenetic memory, not only are important in mammalian development but also play a key role in AML disease biology. In addition to their classical canonical antagonistic transcriptional functions, noncanonical synergistic and nontranscriptional functions of PcG and TrxG are emerging. Here, we review the biochemical properties of major mammalian PcG and TrxG complexes and their roles in AML disease biology, including disease maintenance as well as drug resistance. We summarize current efforts on targeting PcG and TrxG for treatment of AML and propose rational synthetic lethality and drug-induced antagonistic pleiotropy options involving PcG and TrxG as potential new therapeutic avenues for treatment of AML.

Highlights

Acute myeloid leukemia (AML) is a blood cancer characterized by the uncontrolled growth of myeloid blood cells in the bone marrow that interfere with the production and functions of normal blood cells
Aberrant DNA methylation in acute myeloid leukemia (AML) and its clinical implications have been recently reviewed [28, 135]; here, we focus on two major classes of key epigenetic regulators, Polycomb group (PcG) and Trithorax group (TrxG) proteins, which have important functions in the covalent modification and remodeling of chromatin involved in AML biology
H2AK119ub mediated by PRC1.4 is facilitated by polybromo- and Brg-associated factors (PBAF) complexes, revealing a synergism between PcG and TrxG complexes in gene silencing at sites of DNA damage and recruitment of DNA damage response (DDR) proteins

Summary

Introduction

Acute myeloid leukemia (AML) is a blood cancer characterized by the uncontrolled growth of myeloid blood cells in the bone marrow that interfere with the production and functions of normal blood cells. H2AK119ub mediated by PRC1.4 is facilitated by PBAF complexes, revealing a synergism between PcG and TrxG complexes in gene silencing at sites of DNA damage and recruitment of DDR proteins.

Results

Conclusion