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

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

Research output: Contribution to journalArticlepeer-review

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;NrasG12D; 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.

Original languageEnglish
Pages (from-to)2392-2403
Number of pages12
JournalBlood
Volume126
Issue number21
DOIs
Publication statusPublished - Nov 19 2015

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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