期刊
GENES & DEVELOPMENT
卷 33, 期 1-2, 页码 61-74出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.319830.118
关键词
taspase1; TASP1; MLL1; KMT2A; protein stability; CKII; CX-4945; regulation of gene expression
资金
- National Institutes of Health (NIH)/National Cancer Institute (NCI) [T32 CA070085]
- Alex's Lemonade Stand Foundation (ALSF) Young Investigator Award by ALSF
- Training Program in Signal Transduction and Cancer [T32-CA070085]
- NCI [R50-CA221848, R35-CA197569]
- Northwestern Mutual
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 taspasel, 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 taspasel cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspasel-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.
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