Cross-talk between retinoic acid and STAT3 signaling pathways in acute promyelocytic leukemia

Leuk Lymphoma. 2003 Dec;44(12):2023-9. doi: 10.1080/1042819031000116670.

Abstract

Acute promyelocytic leukemia (APL) is a form of acute myelogenous leukemia characterized by chromosomal alterations involving the retinoic acid receptor-alpha (RARalpha) gene that generate unique chimeric proteins (N-RARalpha) and by clinical responsiveness to all-trans-retinoic acid (ATRA) treatment. APL cells are notable for differentiation block and resistance to apoptosis. While increasing evidence suggests that N-RARalpha fusion proteins interfere with normal RARalpha transcription function at retinoic acid response elements (RAREs) resulting in inhibition of normal myeloid differentiation, the mechanism for apoptosis resistance remains unexplained. Recently, we and others have reported that APL-fusion proteins can augment STAT3 transcriptional activity. Constitutive STAT3 activation has been observed in a number of hematopoietic and non-hematopoietic malignancies where it contributes to apoptosis resistance. In this review, we summarize a series of recent observations concerning cross talk between the retinoic acid and STAT3 signaling pathways in APL cells. These findings support the hypothesis that apoptosis resistance in APL may be mediated through the effects of APL fusion proteins on STAT3 signaling and suggest that targeting of STAT3 may be a useful adjunctive treatment strategy in APL.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Apoptosis
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Leukemia, Promyelocytic, Acute / embryology*
  • Models, Biological
  • Protein Structure, Tertiary
  • Receptors, Retinoic Acid / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Retinoic Acid Receptor alpha
  • STAT3 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / metabolism*
  • Tretinoin / metabolism*
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Retinoic Acid Receptor alpha
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Tretinoin