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Genes Dev. 2019 Jan 1;33(1-2):61-74. doi: 10.1101/gad.319830.118. Epub 2018 Dec 20.

Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia.

Author information

1
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
2
Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
3
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
4
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
5
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208, USA.
6
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

Abstract

Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.

KEYWORDS:

CKII; CX-4945; KMT2A; MLL1; TASP1; protein stability; regulation of gene expression; taspase1

PMID:
30573454
PMCID:
PMC6317322
DOI:
10.1101/gad.319830.118
[Indexed for MEDLINE]
Free PMC Article

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