title: Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies.
abstract: Histone deacetylase (HDAC) inhibitors (HDACis) have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat, and panobinostat are Food and Drug Administration-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 HDACis in 3 genetically distinct leukemias and lymphomas. Individual Hdacs were depleted in murine acute myeloid leukemias (MLL-AF9;Nras(G12D); PML-RARα acute promyelocytic leukemia [APL] cells) and Eµ-Myc lymphoma in vitro and in vivo. Strikingly, Hdac3-depleted cells were selected against in competitive assays for all 3 tumor types. Decreased proliferation following Hdac3 knockdown was not prevented by BCL-2 overexpression, 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 codepletion 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 codepletion 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.
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Matthews
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy;
authors.forename: Parinaz
authors.initials: P
authors.lastname: Mehdipour
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Leonie A
authors.initials: LA
authors.lastname: Cluse
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Falkenberg
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY;
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria;
authors.forename: Mareike
authors.initials: M
authors.lastname: Roth
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy;
authors.forename: Fabio
authors.initials: F
authors.lastname: Santoro
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Eva
authors.initials: E
authors.lastname: Vidacs
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Kym
authors.initials: K
authors.lastname: Stanley
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Colin M
authors.initials: CM
authors.lastname: House
authors.affiliation: Repligen Corporation, Waltham, MA;
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY;
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria;
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; Drug Development Program, European Institute of Oncology, Milan, Italy; and Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C052617:Bcl2 protein, mouse; D006655:Histone Deacetylases