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.
Original language | English (US) |
---|---|
Pages (from-to) | 61-74 |
Number of pages | 14 |
Journal | Genes and Development |
Volume | 33 |
Issue number | 1-2 |
DOIs | |
State | Published - Jan 1 2019 |
Funding
We are grateful to Dr. Edwin Smith for critical reading of the manuscript. We are also grateful to Anna Whelan and Michaela Twar-ogova for technical assistance in preparation of recombinant taspase1. Z.Z. is supported in part by National Institutes of Health (NIH)/National Cancer Institute (NCI) training grant T32 CA070085 and Alex’s Lemonade Stand Foundation (ALSF) Young Investigator Award by ALSF and Northwestern Mutual. L.W. is supported by the Training Program in Signal Transduction and Cancer (T32-CA070085). E.T.B. is supported by Research Specialist Award R50-CA221848 from the NCI. Studies in regard to the role of the MLL/COMPASS family of histone methyltransfer-ases in leukemic pathogenesis are supported in part by the generous Outstanding Investigator Award (R35-CA197569) from the NCI to A.S.
Keywords
- CKII
- CX-4945
- KMT2A
- MLL1
- Protein stability
- Regulation of gene expression
- TASP1
- Taspase1
ASJC Scopus subject areas
- Genetics
- Developmental Biology