| First Author | Prunier C | Year | 2015 |
| Journal | Cell Rep | PubMed ID | 25683711 |
| Mgi Jnum | J:222039 | Mgi Id | MGI:5643885 |
| Doi | 10.1016/j.celrep.2015.01.024 | Citation | Prunier C, et al. (2015) Disruption of the PHRF1 Tumor Suppressor Network by PML-RARalpha Drives Acute Promyelocytic Leukemia Pathogenesis. Cell Rep |
| abstractText | PHRF1 functions as an essential component of the TGF-beta 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-beta receptor. In acute promyelocytic leukemia (APL), acquisition of PML-RARalpha is known to impede critical aspects of TGF-beta 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-RARalpha 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-beta 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-RARalpha represents a critical determinant in APL pathogenesis. |
