title: Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL.
abstract: OBJECTIVE
  Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small-molecule inhibitors that target epigenetic mechanisms.
  
  
  METHODS
  A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform-specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B-cell malignancy-derived cell lines and a pediatric B-ALL were used to demonstrate pharmacologic efficacy.
  
  
  RESULTS
  Nonselective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform-specific HDACi indicated that targeting HDAC1-3 with class I HDAC-specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA-mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo, whereas it was far less effective against other B-cell-derived malignancies.
  
  
  CONCLUSIONS
  Here, we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL.
authors: Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts. mstubbs@incyte.com.
authors: Matthew C
authors: MC
authors: Stubbs
authors: Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts.
authors: Wonil
authors: W
authors: Kim
authors: Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts.
authors: Megan
authors: M
authors: Bariteau
authors: Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts.
authors: Tina
authors: T
authors: Davis
authors: Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts.
authors: Sridhar
authors: S
authors: Vempati
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Janna
authors: J
authors: Minehart
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Matthew
authors: M
authors: Witkin
authors: Department of Medical Oncology, Dana-Farber-Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors: Jun
authors: J
authors: Qi
authors: Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Andrei V
authors: AV
authors: Krivtsov
authors: Department of Medical Oncology, Dana-Farber-Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors: James E
authors: JE
authors: Bradner
authors: Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts. Harvard Stem Cell Institute, Boston, Massachusetts.
authors: Andrew L
authors: AL
authors: Kung
authors: Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Harvard Stem Cell Institute, Boston, Massachusetts.
authors: Scott A
authors: SA
authors: Armstrong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases