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

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2015 Feb 17

PMID 25683711

Citations 13

Authors

Celine Prunier

Ming-Zhu Zhang

Santosh Kumar

Laurence Levy

Olivier Ferrigno

Guri Tzivion

Azeddine Atfi

Affiliations

Soon will be listed here.

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.

Citing Articles

Mono-ubiquitination of TopBP1 by PHRF1 enhances ATR activation and genomic stability.

Zhao F, Cai C, Gao H, Moon J, Christyani G, Qin S Nucleic Acids Res. 2025; 53(5).

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Histone H3 N-terminal recognition by the PHD finger of PHRF1 is required for proper DNA damage response.

Jain K, Kougnassoukou Tchara P, Mengistalem A, Holland A, Bowman C, Marunde M bioRxiv. 2024; .

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Cellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia.

Jin W, Dai Y, Chen L, Zhu H, Dong F, Zhu H Nat Commun. 2024; 15(1):1423.

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PHRF1 promotes the class switch recombination of IgA in CH12F3-2A cells.

Lee J, Chou N, Yu Y, Shih H, Lin H, Lee C PLoS One. 2023; 18(8):e0285159.

PMID: 37540725 PMC: 10403053. DOI: 10.1371/journal.pone.0285159.

A novel network pharmacology approach for leukaemia differentiation therapy using Mogrify.

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