MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity.
Anna SkuchaJessica EbnerJohannes SchmöllerlMareike RothThomas EderAdrián César-RazquinAlexey StukalovSarah VittoriMatthias MuharBin LuMartin AichingerJulian JudeAndré C MüllerBalázs GyőrffyChristopher R VakocPeter ValentKeiryn L BennettJohannes ZuberGiulio Superti-FurgaFlorian GrebienPublished in: Nature communications (2018)
MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins. Functional investigation of 128 conserved MLL-fusion-interactors identifies a specific role for the lysine methyltransferase SETD2 in MLL-leukemia. SETD2 loss causes growth arrest and differentiation of AML cells, and leads to increased DNA damage. In addition to its role in H3K36 tri-methylation, SETD2 is required to maintain high H3K79 di-methylation and MLL-AF9-binding to critical target genes, such as Hoxa9. SETD2 loss synergizes with pharmacologic inhibition of the H3K79 methyltransferase DOT1L to induce DNA damage, growth arrest, differentiation, and apoptosis. These results uncover a dependency for SETD2 during MLL-leukemogenesis, revealing a novel actionable vulnerability in this disease.
Keyphrases
- acute myeloid leukemia
- dna damage
- allogeneic hematopoietic stem cell transplantation
- protein protein
- genome wide
- oxidative stress
- dna methylation
- cell cycle arrest
- single cell
- cell death
- escherichia coli
- bone marrow
- climate change
- induced apoptosis
- dna repair
- transcription factor
- endoplasmic reticulum stress
- cystic fibrosis
- cross sectional
- pseudomonas aeruginosa
- hepatitis c virus
- long noncoding rna
- biofilm formation
- antiretroviral therapy
- pi k akt
- candida albicans