Regulation of S100A10 by the PML-RAR-α oncoprotein

Paul A O'Connell, Patricia A Madureira, Jason N Berman, Robert S Liwski, David M Waisman

Research output: Contribution to journalArticlepeer-review


Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia that results from the expression of the promyelocytic leukemia-retinoic acid receptor α (PML-RAR-α) oncoprotein. It is characterized by severe hemorrhagic complications due in part to excessive fibrinolysis, resulting from the excessive generation of the fibrinolytic enzyme, plasmin, at the cell surface of the PML cells. The treatment of patients with all-trans retinoic acid (ATRA) effectively ameliorates the disease by promoting the destruction of the PML-RAR-α oncoprotein. In the present study we show for the first time that the plasminogen receptor, S100A10, is present on the extracellular surface of APL cells and is rapidly down-regulated in response to all-trans retinoic acid. The loss of S100A10 is concomitant with a loss in fibrinolytic activity. Furthermore, the induced expression of the PML-RAR-α oncoprotein increased the expression of cell surface S100A10 and also caused a dramatic increase in fibrinolytic activity. Depletion of S100A10 by RNA interference effectively blocked the enhanced fibrinolytic activity observed after induction of the PML-RAR-α oncoprotein. These experiments show that S100A10 plays a crucial role in the generation of plasmin leading to fibrinolysis, thus providing a link to the clinical hemorrhagic phenotype of APL.

Original languageEnglish
Pages (from-to)4095-4105
Number of pages11
Issue number15
Publication statusPublished - 14 Apr 2011


  • Annexin A2/genetics
  • Antineoplastic Agents/pharmacology
  • Down-Regulation/drug effects
  • Fibrinolysin/metabolism
  • Fibrinolysis/physiology
  • Humans
  • Leukemia, Promyelocytic, Acute/genetics
  • Membrane Proteins/genetics
  • Oncogene Proteins, Fusion/genetics
  • Phenotype
  • Plasminogen/metabolism
  • S100 Proteins/genetics
  • Tretinoin/pharmacology
  • U937 Cells


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