Matthews, G. M., Mehdipour, P., Cluse, L. A., Falkenberg, K. J., Wang, E., Roth, M., Santoro, F., Vidacs, E., Stanley, K., House, C. M., Rusche, J. R., Vakoc, C. R., Zuber, J., Minucci, S., Johnstone, R. W. (November 2015) Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies. Blood, 126 (21). pp. 2392-2403. ISSN 1528-0020 (Electronic)0006-4971 (Linking)
Abstract
Histone deacetylase inhibitors have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat and panobinostat are FDA-approved for hematological malignancies and inhibit class II and/or class I HDACs including HDAC1, 2, 3 and 6. We combined genetic and pharmacological approaches to investigate whether suppression of individual or multiple Hdacs phenocopied broad-acting HDACi in three genetically distinct leukemias and lymphomas. Individual Hdacs were depleted in murine AMLs (MLL-AF9;NrasG12D; PML-RARalpha APL) and Emu-Myc lymphoma in vitro and in vivo. Strikingly, Hdac3-depleted cells were selected against in competitive assays for all three tumor types. Decreased proliferation following Hdac3 knockdown was not prevented by BCL-2 over-expression, caspase inhibition or knockout of Cdkn1a in Emu-Myc lymphoma and depletion of Hdac3 in vivo significantly reduced tumor burden. Interestingly, APL cells depleted of Hdac3 demonstrated a more differentiated phenotype. Consistent with these genetic studies, the HDAC3 inhibitor RGFP966 reduced proliferation of Emu-Myc lymphoma and induced differentiation in APL. Genetic co-depletion of Hdac1 with Hdac2 was pro-apoptotic in Emu-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233. This study demonstrates the importance of HDAC3 for the proliferation of leukemia and lymphoma cells suggesting that HDAC3-selective inhibitors could prove useful for the treatment of hematological malignancies. Moreover, our results demonstrate that co-depletion of Hdac1 with Hdac2 mediates a robust pro-apoptotic response. Our integrated genetic and pharmacological approach provides important insights into the individual or combinations of HDACs that could be prioritized for targeting in a range of hematological malignancies.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > histone deacetylase |
| CSHL Authors: | |
| Communities: | CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | 19 November 2015 |
| Date Deposited: | 20 Oct 2015 19:25 |
| Last Modified: | 05 Nov 2020 16:53 |
| PMCID: | PMC4653767 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/31936 |
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