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Unraveling MLL1-fusion Leukemia: Epigenetic Revelations from an iPS Cell Point Mutation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Our understanding of acute leukemia pathology is heavily dependent on 11q23 chromosomal translocations involving the mixed lineage leukemia-1 (MLL1) gene, a key player in histone H3 lysine 4 (H3K4) methylation. These translocations result in distinct MLL1-fusion (MLL1F) proteins that are thought to drive leukemogenesis. However, the mechanism behind increased H3K4 trimethylation in MLL1F-leukemic stem cells (MLL1F-LSCs), following loss of catalytic SET domain of MLL1 (known for H3K4 mono- and dimethylation), remains unclear. In our investigation, we introduced a homozygous loss-of-function point mutation in MLL1 within human induced pluripotent stem cells. Remarkably, this mutation mimics the histone methylation, gene expression, and EMT phenotypes of MLL1F-LSCs- without the need for a translocation or functional wild-type MLL1. This observation underscores the essential role of MLL1's enzymatic activity in restraining the cascade of epigenetic changes associated with the gene activating H3K4 trimethylation mark, which we show is catalyzed by mislocalized SETd1a H3K4 trimethyltransferase in the absence of MLL1’s enzymatic activity. Challenging existing models, our findings imply that MLL1F-induced leukemias arise from a dominant-negative impact on MLL1's histone methyltransferase activity. We advocate for a therapeutic paradigm shift, targeting SETd1a for precision medicine. This work opens new avenues for addressing the complexities of MLL1-associated leukemias and improving targeted therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213239 | GEO | 2024/09/09

REPOSITORIES: GEO

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Project description:Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. The Set1/COMPASS was the founding member and the only H3K4 methylases in S. cerevisiae, however, in mammals at least six H3K4 methylases Set1A/B and MLL1-4 are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation pattern in wild-type Mll1+/+ and Mll1-/- mouse fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, Menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/4 and/or the Set1 complexes have little to no effect on the Hox loci H3K4 methylation or expression levels in these MEFs. Together these data provide insight into redundancy and specialization of COMPASS-like complexes in mammals and provide evidence on a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation. Chromatin Immunoprecipitation was performed with antibodies for histone 3 lysine 4 trimethylation, histone 3, and PolII in Mll1+/+ and Mll1-/- mouse embryonic fibroblasts. DNA was hybridized to a custom Agilent tiling array (4x44k format) that covers three of the hox regions (A,B,D) and a collection of other genes.

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Unraveling MLL1-fusion Leukemia: Epigenetic Revelations from an iPS Cell Point Mutation

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