Salt-Inducible Kinase inhibition suppresses acute myeloid leukemia progression in vivo

Tarumoto, Y., Lin, S., Wang, J., Milazzo, J. P., Xu, Y., Lu, B., Yang, Z., Wei, Y., Polyanskaya, S., Wunderlich, M., Gray, N. S., Stegmaier, K., Vakoc, C. R. (November 2019) Salt-Inducible Kinase inhibition suppresses acute myeloid leukemia progression in vivo. Blood. ISSN 0006-4971

URL: https://www.ncbi.nlm.nih.gov/pubmed/31697837
DOI: 10.1182/blood.2019001576

Abstract

Lineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a Salt-Inducible Kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF MEF2C. In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C. Here, we evaluated whether inhibition of SIK3 with the tool compound YKL-05-099 can suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells under in vitroand in vivoconditions. Similar phenotypes were obtained when exposing cells to YKL-05-099, which caused cell cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. Using a gatekeeper allele of SIK3, we found that the anti-proliferative effects of YKL-05-099 occurred through on-target inhibition of SIK3 kinase activity. Based on these findings, we treated two different mouse models of MLL-AF9 AML with YKL-05-099, which attenuated disease progression in vivoand extended animal survival at well-tolerated doses. These findings validate SIK3 as a therapeutic target in MEF2C-addicted AML and provide a rationale for developing drug-like inhibitors of SIK3 for definitive pre-clinical investigation and for studies in human patients.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Vakoc lab
Depositing User: Adrian Gomez
Date: 1 November 2019
Date Deposited: 20 Nov 2019 19:32
Last Modified: 20 Nov 2019 19:32
Related URLs:
URI: http://repository.cshl.edu/id/eprint/38722

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