title: Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex.
abstract: An exciting recent approach to targeting transcription factors in cancer is to block formation of oncogenic complexes. We investigated whether interfering with the interaction of the transcription factor SALL4, which is critical for leukemic cell survival, and its epigenetic partner complex represents a novel therapeutic approach. The mechanism of SALL4 in promoting leukemogenesis is at least in part mediated by its repression of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through its interaction with a histone deacetylase (HDAC) complex. In this study, we demonstrate that a peptide can compete with SALL4 in interacting with the HDAC complex and reverse its effect on PTEN repression. Treating SALL4-expressing malignant cells with this peptide leads to cell death that can be rescued by a PTEN inhibitor. The antileukemic effect of this peptide can be confirmed on primary human leukemia cells in culture and in vivo, and is identical to that of down-regulation of SALL4 in these cells using an RNAi approach. In summary, our results demonstrate a novel peptide that can block the specific interaction between SALL4 and its epigenetic HDAC complex in regulating its target gene, PTEN. Furthermore, targeting SALL4 with this approach could be an innovative approach in treating leukemia.
authors.affiliation: Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Gao
authors.forename: Todor
authors.initials: T
authors.lastname: Dimitrov
authors.forename: Kol Jia
authors.initials: KJ
authors.lastname: Yong
authors.forename: Hiro
authors.initials: H
authors.lastname: Tatetsu
authors.forename: Ha-won
authors.initials: HW
authors.lastname: Jeong
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Li
authors.initials: L
authors.lastname: Chai
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular; D015195:Drug Design; D016889:Endometrial Neoplasms; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects* / Q000502:physiology; D018922:HL-60 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007948:Leukemia, Monocytic, Acute; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010446:Peptide Fragments; C472575:SALL4 protein, human; D014157:Transcription Factors; C012589:trichostatin A; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2