MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity

Skucha, A., Ebner, J., Schmöllerl, J., Roth, M., Eder, T., César-Razquin, A., Stukalov, A., Vittori, S., Muhar, M., Lu, B., Aichinger, M., Jude, J., Müller, A. C., Győrffy, B., Vakoc, C. R., Valent, P., Bennett, K. L., Zuber, J., Superti-Furga, G., Grebien, F. (May 2018) MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. Nat Commun, 9 (1). p. 1983. ISSN 2041-1723

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DOI: 10.1038/s41467-018-04329-y


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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics and Genomics Program
CSHL labs > Vakoc lab
Depositing User: Matthew Dunn
Date: 18 May 2018
Date Deposited: 14 Dec 2020 18:01
Last Modified: 07 Jun 2021 20:49
PMCID: PMC5959866
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