Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies

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)

URL: http://www.ncbi.nlm.nih.gov/pubmed/26447190
DOI: 10.1182/blood-2015-03-632984

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
Depositing User: Matt Covey
Date: 19 November 2015
Date Deposited: 20 Oct 2015 19:25
Last Modified: 14 Dec 2015 20:26
PMCID: PMC4653767
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31936

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