Disruption of the PHRF1 Tumor Suppressor Network by PML-RARα Drives Acute Promyelocytic Leukemia Pathogenesis

Céline Prunier,Ming-Zhu Zhang,Santosh Kumar,Laurence Levy,Olivier Ferrigno,Guri Tzivion,Azeddine Atfi

doi:10.1016/j.celrep.2015.01.024

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.

Highlights

The PML tumor suppressor plays an important role in constraining both hematological and non-hematological malignancies, yet much remains to be learned about how it is regulated or how it might be inactivated during tumor progression (de The et al, 2012; Dos Santos et al, 2013)
Our published data that TGIF restricts TGF-β signaling by antagonizing cPML prompted us to explore whether PML-RARα could disrupt the interplay between TGIF and cPML, in turn endowing leukemia cells with the capability to evade TGF-β cytostatic signaling (Ettahar et al, 2013; Faresse et al, 2008; Seo et al, 2006)
We initially tested this possibility by employing NB4 blasts, which derive from an acute promyelocytic leukemia (APL) patient and exhibit the particularity to undergo proteasomal degradation in response to retinoic acid (RA) (Lanotte et al, 1991; Lin et al, 2004)

Summary

SUMMARY

PHRF1 functions as an essential component of the TGF-β tumor suppressor pathway by triggering degradation of the homeodomain transcription factor TGIF. This leads to redistribution of cPML into the cytoplasm, where it coordinates phosphorylation and activation of Smad 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. These defects are thought to rely on suppression of cPML activity, the mechanisms underlying this phenomenon remain enigmatic. 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

INTRODUCTION

RESULTS AND DISCUSSION

Concluding Remarks

EXPERIMENTAL PROCEDURES