COMPASS Ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer

Abstract

The KMT2 (lysine methyltransferase) family of histone modifying proteins play essential roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many blood and solid tumor cancers. The KMT2A-D proteins are histone 3 lysine 4 (H3K4) methyltransferases embedded in large COMPASS-like complexes important for RNA Polymerase II-dependent transcription. KMT2 mutations were initially associated with pediatric Mixed Lineage Leukemias (MLL) and found to be the result of rearrangements of the MLL1/KMT2A gene at 11q23. Over the past several years, large-scale tumor DNA sequencing studies have revealed the potential involvement of other KMT2 family genes, including heterozygous somatic mutations in the paralogous MLL3/KMT2C and MLL2(4)/KMT2D genes that are now among the most frequently associated with human cancer. Recent studies have provided a better understanding of the potential roles of disrupted KMT2C and KMT2D family proteins in cell growth aberrancy. These findings, together with an examination of cancer genomics databases provide new insights into the contribution of KMT2C/D proteins in epigenetic gene regulation and links to carcinogenesis.

Keywords: Chromatin; Co-occurrence; Epigenetic; Lysine methyltransferase.

Figure 1. Human COMPASS-like complexes and their histone targets.

Two COMPASS-like families of complexes exist in higher eukaryotes, we indicate as MLX (MLL-TRX) and MLR (MLL-TRR) with distinct, though potentially limited overlapping target specificity. The MLX and MLR family complexes all contain catalytic subunits that methylate nucleosomes on histone 3 lysine 4 (H3K4) to produce di/trimethylation (H3K4me2/3; MLX family) or monomethylation (H3K4me1; MLR family). These histone modifications are associated with gene promoters and enhancers, respectively, and are linked to the activation of gene transcription. The MLX and MLR complexes both contain a set of core components (WDR5, RBBP5, ASH2 and hDPY30), as well as unique subunits. The MLX complexes contain Menin and HCF1 subunits, while the MLR complexes contain the histone lysine demethylase UTX, PTIP, PA1 and NCOA6.

Figure 2. Organization and mutation clustering of the KMT2A-D family proteins.

A) The KMT2A-D proteins are enormous (2715–5265aa), and each contains multiple domains, including Plant Homeodomain (PHD), SET/Post-SET methyltransferase, FY-rich (FYR) regions, as well as domains that are specific for each member or family. The KMT2A/B proteins are cleaved post-translationally by the taspase protease; although, there is no known cleavage of the mature KMT2C/D proteins. The PHD domain cluster in KMT2A/B is highly related to the PHD ‘b’ domain cluster in KMT2C/D. The black diamonds represent putative nuclear receptor (NR) binding motifs (LLXXL, LXXLL). Data obtained from The Cancer Genome Atlas (TCGA) was used to map cancer associated mutations in each protein and to identify mutational hotspots by binning based on mutation type (missense/nonsense), suggesting important functional protein domains [13, 31]. B) KMT2C and KMT2D are among the most frequently mutated cancer associated genes. Cancer mutation data was obtained from the NCI Genomic Data Commons Portal (GDC) that represents a summary of over 33,000 cases, including The Cancer Genome Atlas (TCGA) data. The top 20 most frequently mutated genes are shown together with the percent of cases affected across multiple cancer types.

Figure 3. KMT2C/D involvement in lung cancer development and survival.

A) K-M plotter analysis of the correlation between KMT2C and KMT2D transcript expression and survival probability among lung adenocarcinoma patients. Low expression of both genes is correlated with shorter overall survival time. B) Association of KMT2C and KMT2D mutations with lung cancer type, stage of first detection and overall patient survival. Data was obtained from the cBio Portal, analyzing 1144 patients with lung adenocarcinoma or squamous cell carcinoma. Staging is according to the American Joint Committee on Cancer (AGCC). Truncating mutations of KMT2D are commonly observed in early stage lung squamous cell carcinomas, suggesting driver function; whereas, missense mutations in KMT2C are common in early stage lung adenocarcinomas.