title: Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivo.
abstract: BACKGROUND
  Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have been proposed as potential new therapies for lymphoid malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma for which standard first line treatment is the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). The HDACi valproate, which has for long been utilized in anti-convulsive therapy, has been shown to sensitize to chemotherapy in vitro. Valproate upregulates expression of CD20 in lymphoma cell lines; therefore, 48 hour pre-treatment with valproate before first line R-CHOP in DLBCL stages II-IV is evaluated in the phase I clinical trial VALFRID; Valproate as First line therapy in combination with Rituximab and CHOP in Diffuse large B-cell lymphoma.
  
  
  RESULTS
  Pretreatment with valproate at oral doses comparable to anti-convulsive therapy, resulted in upregulation of CD20 mRNA and CD20 protein on the cell surface as measured by qPCR and FACS analysis in lymphoma biopsies from three evaluated patients from the VALFRID study. Valproate-treatment corresponded to increased acetylation of Histone3Lysine9 (H3K9ac) in peripheral blood mononuclear cells (PBMCs), which were employed as surrogate tissue for valproate-related epigenetic modifications.
  
  
  CONCLUSIONS
  Valproate treatment at pharmacologically relevant doses resulted in upregulation of CD20 in vivo, and also in expected epigenetic modifications. This suggests that pre-treatment with valproate or other HDACis before anti-CD20 therapy could be advantageous in CD20-low B-cell lymphomas. Further studies are warranted to evaluate this conclusion.
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Jesper Kofoed
authors.initials: JK
authors.lastname: Damm
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gordon
authors.affiliation: Department of Pathology, Skåne University Hospital, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.affiliation: Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Jerkeman
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Urban
authors.initials: U
authors.lastname: Gullberg
authors.affiliation: Stem Cell Center (SCC), Lund University, Lund, Sweden.
authors.forename: Anne
authors.initials: A
authors.lastname: Hultquist
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Drott
keywords: CD20; DLBCL; HDACi; Rituximab; Valproate; Valproic acid