title: Inactivation of HDAC1 or HDAC2 induces gamma globin expression without altering cell cycle or proliferation.
abstract: Other than hydroxyurea, no pharmacologic agents are clinically available for fetal hemoglobin (HbF) induction in sickle cell disease (SCD). An optimal candidate would induce HbF without causing cell cycle inhibition and would act independently of hydroxyurea in order to yield additional HbF induction when combined. We explored whether inhibition of histone deacetylase (HDAC) 1 or HDAC2 could achieve these goals. In human erythroid progenitor cells, shRNA knockdown of the HDAC1 or HDAC2 genes induced gamma globin, without altering cellular proliferation in vitro, and without altering cell cycle phase. Treatment with hydroxyurea in combination with HDAC2 knockdown yielded a further increase in gamma globin expression. Additionally, when CD34+ cells were treated with both hydroxyurea and MS-275 (an inhibitor of HDAC 1, 2, and 3), an additive induction of relative gamma globin expression was achieved. Our findings support further clinical investigation of HDAC inhibitors in combination with hydroxyurea in SCD patients.
authors: Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.|Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Erica B
authors: EB
authors: Esrick
authors: Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Marie
authors: M
authors: McConkey
authors: Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Katherine
authors: K
authors: Lin
authors: Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Alyse
authors: A
authors: Frisbee
authors: Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Benjamin L
authors: BL
authors: Ebert
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D002454:Cell Differentiation; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D016086:Lentivirus / Q000235:genetics; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism; D055545:gamma-Globins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D055544:beta-Globins; D055545:gamma-Globins; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006918:Hydroxyurea