THE ROLE OF THE CELL SURFACE PROTEASE RECEPTOR S100A10 IN ACUTE PROMYELOCYTIC LEUKEMIA (APL) AND ITS REGULATION BY RETINOIC ACID THERAPY

Abstract

Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia, is characterized by expression of the promyelocytic leukemia-retinoic acid receptor oncoprotein, PML/RARα, which blocks granulocyte differentiation. Patients with APL present fatal hemorrhagic complications from excessive generation of the fibrinolytic protease plasmin and the procoagulant protein, tissue factor (TF). We previously demonstrated that a cell surface regulator of plasmin generation, S100A10 (p11) is upregulated in APL promyelocytes. Treatment of APL promyelocytes with all-trans retinoic acid (ATRA) mitigates the hemorrhagic disorder concomitant with promoting the degradation of PML/RARα and p11. Here, we show PML/RARα up-regulates p11 transcript and protein levels concomitant with increased plasmin activity. Depletion of p11 from the PML/RARα expressing APL promyelocyte cell line, NB4, reduced plasmin activity, but not TF activity. ATRA treatment of NB4 cells reduced p11 transcripts and promoted its ubiquitin-independent proteasomal degradation. Unexpectedly, the ATRA-dependent loss of p11 increased the plasmin activity and decreased the TF activity of the NB4 cells. However, ATRA treatment of MCF-7 cells also blocked p11 transcription and protein levels suggesting that ATRA can regulate p11 levels independent of PML/RARα. These studies highlight the complex regulation of p11, demonstrate that changes in p11 do not always correspond with decreases in plasmin generation, and challenge the hypothesis that p11 is regulated by ubiquitin-mediated proteasomal degradation.