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RAR?-PLZF oncogene inhibits C/EBP? function in myeloid cells.

ABSTRACT: In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor ? (PLZF-RAR?) and RAR?-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein ? (C/EBP?), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RAR?-PLZF inhibits myeloid cell differentiation through interactions with C/EBP? tethered to DNA, using ChIP and DNA capture assays. Furthermore, RAR?-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBP? target loci, thereby decreasing the expression of C/EBP? target genes. In line with these results, HDAC inhibitors restore in part C/EBP? target gene expression. These findings provide molecular evidence for a mechanism through which RAR?-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBP? and inhibiting its activity.

SUBMITTER: Girard N

PROVIDER: S-EPMC3746863 | biostudies-other | 2013 Aug

REPOSITORIES: biostudies-other

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RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells.

Girard Nathalie N Tremblay Mathieu M Humbert Magali M Grondin Benoît B Haman André A Labrecque Jean J Chen Bing B Chen Zhu Z Chen Sai-Juan SJ Hoang Trang T

Proceedings of the National Academy of Sciences of the United States of America 20130729 33

In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the ...[more]

PMID: 23898169

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Project description:BackgroundWe previously demonstrated that the HLA class II transactivator CIITA inhibits HIV-1 replication in T cells by competing with the viral transactivator Tat for the binding to Cyclin T1 subunit of the P-TEFb complex. Here, we analyzed the anti-viral function of CIITA in myeloid cells, another relevant HIV-1 target cell type. We sinvestigated clones of the U937 promonocytic cell line, either permissive (Plus) or non-permissive (Minus) to HIV-1 replication. This different phenotype has been associated with the expression of TRIM22 in U937 Minus but not in Plus cells.MethodsU937 Plus cells stably expressing CIITA were generated and HLA-II positive clones were selected by cell sorting and cloning. HLA and CIITA proteins were analyzed by cytofluorometry and western blotting, respectively. HLA-II DR and CIITA mRNAs were quantified by qRT-PCR. Tat-dependent transactivation was assessed by performing the HIV-1 LTR luciferase gene reporter assay. Cells were infected with HIV-1 and viral replication was evaluated by measuring the RT activity in culture supernatants.ResultsCIITA was expressed only in HLA-II-positive U937 Minus cells, and this was strictly correlated with inhibition of Tat-dependent HIV-1 LTR transactivation in Minus but not in Plus cells. Overexpression of CIITA in Plus cells restored the suppression of Tat transactivation, confirming the inhibitory role of CIITA. Importantly, HIV-1 replication was significantly reduced in Plus-CIITA cells with respect to Plus parental cells. This effect was independent of TRIM22 as CIITA did not induce TRIM22 expression in Plus-CIITA cells.ConclusionsU937 Plus and Minus cells represent an interesting model to study the role of CIITA in HIV-1 restriction in the monocytic/macrophage cell lineage. The differential expression of CIITA in CIITA-negative Plus and CIITA-positive Minus cells correlated with their capacity to support or not HIV-1 replication, respectively. In Minus cells CIITA targeted the viral transactivator Tat to inhibit HIV-1 replication. The generation of Plus-CIITA cells was instrumental to demonstrate the specific contribution of CIITA in terms of inhibition of Tat activity and HIV-1 restriction, independently from other cellular factors, including TRIM22. Thus, CIITA acts as a general restriction factor against HIV-1 not only in T cells but also in myeloid cells.

Dataset Information

RAR?-PLZF oncogene inhibits C/EBP? function in myeloid cells.

Publications

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells.

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