Pan-Cancer MLL3 Mutational Landscape and Its Association with Immunotherapy

Translocation-linked Mixed Lineage Leukemia (MLL) genes were discovered ~ 30 years ago and are homologs of Trithorax in Drosophila. MLL3 is a histone methyltransferase catalyzing the monomethylation of histone H3 lysine 4 (H3K4me1), a hallmark for gene enhancers. Although recurrent mutations of MLL3 are reported across a broad spectrum of cancers and MLL3 represents one of the most commonly mutated cancer genes, a pan-cancer-wide portrait of this high-frequency mutational event is still lacking. We report here a comprehensive analysis of MLL3 mutation and its association with molecular, cellular, and clinical features in 33 cancer types. The genetic alterations of MLL3 are primarily driven by point mutations or small INDELs rather than large-scale chromosomal perturbations and exhibit lineage-specific variations, which spontaneously yet heterogeneously impinge on the clinical behaviors of cancers and are intrinsically linked to hot tumor microenvironments, especially in uterine corpus endometrial carcinoma (UCEC) and colon adenocarcinoma (COAD), where MLL3 aberrances surprisingly predict better overall survivals and favorable responses to immunochemotherapy. Concurrent mutation of MLL3 and POLE in UCEC is associated with high immune cell infiltration and immune checkpoint gene expression, endowing the applicability of immune checkpoint inhibitors in these patients. Mouse models with Mll3-ablated colon cancer validate the immunostimulatory trait of Mll3 aberration. Our study provides a pan-cancer spectrum of the MLL3 mutational event and will contribute to the understanding of the genetic evolution and disease management of cancers, especially COAD and UCEC. Mll3WT and Mll3KO CT26 cells for RNA-seq and CUT&Tag, and tumor tissues for single-cell RNA-seq