Structure, Function and Inhibition of Critical Protein-Protein Interactions Involving Mixed Lineage Leukemia 1 and Its Fusion Oncoproteins

Authors

Xin Li
Yongcheng Song

Publication Date

4-6-2021

Journal

Journal of Hematology & Oncology

DOI

10.1186/s13045-021-01057-7

PMID

33823889

PMCID

PMC8022399

PubMedCentral® Posted Date

4-6-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Leukemia, Oncogene Proteins, Fusion, Protein Interaction Maps, Mixed lineage leukemia 1, MLL1-rearranged leukemia, Protein–protein interactions, Protein structure, Drug discovery, Protein inhibition

Abstract

Mixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5-10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains of MLL1 fused with one of > 70 fusion partners, among which transcription cofactors AF4, AF9 and its paralog ENL, and ELL are the most frequent. Wild-type (WT)- and onco-MLL1 involve numerous protein-protein interactions (PPI), which play critical roles in regulating gene expression in normal physiology and leukemia. Moreover, WT-MLL1 has been found to be essential for MLL1-rearranged (MLL1-r) leukemia. Rigorous studies of such PPIs have been performed and much progress has been achieved in understanding their structures, structure-function relationships and the mechanisms for activating gene transcription as well as leukemic transformation. Inhibition of several critical PPIs by peptides, peptidomimetic or small-molecule compounds has been explored as a therapeutic approach for MLL1-r leukemia. This review summarizes the biological functions, biochemistry, structure and inhibition of the critical PPIs involving MLL1 and its fusion partner proteins. In addition, challenges and perspectives of drug discovery targeting these PPIs for the treatment of MLL1-r leukemia are discussed.

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