Knockdown of SALL4 Protein Enhances All-trans Retinoic Acid-induced Cellular Differentiation in Acute Myeloid Leukemia Cells

J Biol Chem. 2015 Apr 24;290(17):10599-609. doi: 10.1074/jbc.M114.634790. Epub 2015 Mar 3.


All-trans retinoic acid (ATRA) is a differentiation agent that revolutionized the treatment of acute promyelocytic leukemia. However, it has not been useful for other types of acute myeloid leukemia (AML). Here we explored the effect of SALL4, a stem cell factor, on ATRA-induced AML differentiation in both ATRA-sensitive and ATRA-resistant AML cells. Aberrant SALL4 expression has been found in nearly all human AML cases, whereas, in normal bone marrow and peripheral blood cells, its expression is only restricted to hematopoietic stem/progenitor cells. We reason that, in AMLs, SALL4 activation may prevent cell differentiation and/or protect self-renewal that is seen in normal hematopoietic stem/progenitor cells. Indeed, our studies show that ATRA-mediated myeloid differentiation can be largely blocked by exogenous expression of SALL4, whereas ATRA plus SALL4 knockdown causes significantly increased AML differentiation and cell death. Mechanistic studies indicate that SALL4 directly associates with retinoic acid receptor α and modulates ATRA target gene expression. SALL4 is shown to recruit lysine-specific histone demethylase 1 (LSD1) to target genes and alter the histone methylation status. Furthermore, coinhibition of LSD1 and SALL4 plus ATRA treatment exhibited the strongest anti-AML effect. These findings suggest that SALL4 plays an unfavorable role in ATRA-based regimes, highlighting an important aspect of leukemia therapy.

Keywords: Hematopoietic Stem Cells; Histone Demethylase; Stem Cells; Transcription Corepressor; Tumor Therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Female
  • Gene Knockdown Techniques
  • HL-60 Cells
  • Hematopoietic Stem Cells / metabolism
  • Histone Demethylases / antagonists & inhibitors
  • Histone Demethylases / genetics
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • RNA, Small Interfering / genetics
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tretinoin / pharmacology*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • RARA protein, human
  • RNA, Small Interfering
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • SALL4 protein, human
  • Transcription Factors
  • Tretinoin
  • Histone Demethylases
  • KDM1A protein, human