| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2039855 | Cell Reports | 2015 | 8 Pages |
•PML-RARα stabilizes TGIF by antagonizing PHRF1 activity•PML-RARα and PHRF1 form mutually exclusive complexes with TGIF•Enforced expression of PHRF1 restores TGF-β signaling in APL blasts•Suppression of PHRF1 activity contributes to the pathogenesis of APL
SummaryPHRF1 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.
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