title: Disruption of the PHRF1 Tumor Suppressor Network by PML-RARα Drives Acute Promyelocytic Leukemia Pathogenesis.
abstract: PHRF1 functions as an essential component of the TGF-β tumor suppressor pathway by triggering degradation of the homeodomain repressor factor TGIF. This leads to redistribution of cPML into the cytoplasm, where it coordinates phosphorylation and activation of Smad2 by the TGF-β receptor. In acute promyelocytic leukemia (APL), acquisition of PML-RARα is known to impede critical aspects of TGF-β signaling, including myeloid differentiation. Although these defects are thought to rely on suppression of cPML activity, the mechanisms underlying this phenomenon remain enigmatic. Here, we find that an abnormal function of PML-RARα is to interfere with TGIF breakdown, presumably by competing with PHRF1 for binding to TGIF, culminating in cPML sequestration and inactivation. Enforcing PHRF1 activity is sufficient to restore TGF-β cytostatic signaling in human blasts and suppress APL formation in a mouse model of APL, providing proof-of-concept data that suppression of PHRF1 activity by PML-RARα represents a critical determinant in APL pathogenesis.
authors: Laboratory of Cell Signaling and Carcinogenesis, INSERM UMRS938, 184 Rue du Faubourg St-Antoine, 75571 Paris, France.
authors: Céline
authors: C
authors: Prunier
authors: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
authors: Ming-Zhu
authors: MZ
authors: Zhang
authors: Department of Biochemistry, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USA.
authors: Santosh
authors: S
authors: Kumar
authors: Laboratory of Cell Signaling and Carcinogenesis, INSERM UMRS938, 184 Rue du Faubourg St-Antoine, 75571 Paris, France.
authors: Laurence
authors: L
authors: Levy
authors: Laboratory of Cell Signaling and Carcinogenesis, INSERM UMRS938, 184 Rue du Faubourg St-Antoine, 75571 Paris, France.
authors: Olivier
authors: O
authors: Ferrigno
authors: Department of Biochemistry, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USA.
authors: Guri
authors: G
authors: Tzivion
authors: Laboratory of Cell Signaling and Carcinogenesis, INSERM UMRS938, 184 Rue du Faubourg St-Antoine, 75571 Paris, France; Department of Biochemistry, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USA. Electronic address: azeddine.atfi@inserm.fr.
authors: Azeddine
authors: A
authors: Atfi