Title |
Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies
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Published in |
Blood, October 2015
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DOI | 10.1182/blood-2015-03-632984 |
Pubmed ID | |
Authors |
Geoffrey M Matthews, Parinaz Mehdipour, Leonie A Cluse, Katrina J Falkenberg, Eric Wang, Mareike Roth, Fabio Santoro, Eva Vidacs, Kym Stanley, Colin M House, James R Rusche, Christopher R Vakoc, Johannes Zuber, Saverio Minucci, Ricky W Johnstone |
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;Nras(G12D); PML-RARα APL) and Eμ-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 Eμ-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 Eμ-Myc lymphoma and induced differentiation in APL. Genetic co-depletion of Hdac1 with Hdac2 was pro-apoptotic in Eμ-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. |
X Demographics
Geographical breakdown
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Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Netherlands | 1 | 2% |
Austria | 1 | 2% |
Unknown | 55 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 16 | 28% |
Researcher | 11 | 19% |
Student > Bachelor | 6 | 11% |
Student > Master | 6 | 11% |
Student > Doctoral Student | 4 | 7% |
Other | 9 | 16% |
Unknown | 5 | 9% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 19 | 33% |
Agricultural and Biological Sciences | 14 | 25% |
Medicine and Dentistry | 9 | 16% |
Immunology and Microbiology | 2 | 4% |
Business, Management and Accounting | 2 | 4% |
Other | 3 | 5% |
Unknown | 8 | 14% |