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The mixed lineage leukemia (MLL) gene is involved in numerous chromosomal translocations that result in acute myeloid and acute lymphoid leukemias. The MLL protein belongs to a family of six methyltransferases in mammals that can methylate histone H3 on lysine 4 (H3K4). The methyltransferase activities of MLL and the other family members, SETD1A, SETD1B, MLL2, MLL3 and MLL4, depend on their participation within macromolecular complexes called COMPASS (complex of proteins associated with Set1). Functional diversity within the COMPASS family includes the propensity to mono-, di-, or trimethylate H3K4 and to regulate promoters or enhancers. Recent cancer genome sequencing and animal studies have identified MLL3 and MLL4 as cancer drivers in a wide variety of hematologic and solid tumors. MLL3 and MLL4 implement monomethylation of H3K4 at enhancer regions, whereas another enzyme in MLL3 and MLL4 COMPASS, UTX, which is also frequently mutated in multiple types of cancer, demethylates H3K27me3, a modification associated with transcription repression by the Polycomb group of proteins. Here, we review the different roles for the COMPASS family in cancer and suggest directions for future research toward elucidating the cellular pathways disregulated due to altered COMPASS functions.
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Includes Supplemental Appendixes 1–4, Supplemental Figures 1–3 (also reproduced below), and Supplemental References.
Supplemental Figure 1. Sequencing of 4,742 tumors across 12 cancer types identifies MLL3/4 COMPASS as pan-cancer drivers. X-axis indicates q-value of the most significant tumor type that a factor is frequently mutated. Y-axis indicates the q-value for being frequently mutated across multiple types of cancer. COMPASS subunits are circled in red. MLL is frequently mutated in leukemia but is not significantly mutated in multiple other cancer types. In contrast, MLL3, MLL4 (KMT2D) and their interacting factor the histone demethylase UTX are highly mutated in multiple cell types and are therefore located in the upper right cloud of pan-cancer driver mutations. Figure adapted, with permission from Lawrence et al. (2014).
Supplemental Figure 2. Mutation and amplification of COMPASS proteins across tumors. For each COMPASS gene, the tumor type with the most (blue), second most (orange) and third most (gray) mutations are listed. Mutation frequencies are listed on the y-axis. Mutations (nonsense, missense and frameshift) mutations are listed in the top row and amplifications are listed on the bottom row.
Supplemental Figure 3. Mutations of KMT2B, KMT2C and KDM6A in bladder cancer from the TCGA. 131 bladder tumors were evaluated for mutations. Each individual patient is represented by a column and the COMPASS family subunits MLL3 (KMT2C), MLL4 (MLL2/KMT2D) and UTX (KDM6A) are listed by row. Most patients have only one COMPASS gene affected (74%, 55/74). Figure generated at cBioPortal for Cancer Genomics (Cerami et al., 2012; Gao et al., 2013).