+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on LinkedInFollow on LinkedIn

+ Translate

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

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

Proceedings of the National Academy of Sciences of the United States of America 110(33): 13522-7

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 t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.

(PDF emailed within 0-6 h: $19.90)

Accession: 055333358

Download citation: RISBibTeXText

PMID: 23898169

DOI: 10.1073/pnas.1310067110

Related references

The RARalpha-PLZF oncogene inhibits C/EBPalpha function in myeloid cells. Experimental Hematology (New York) 31(7 Supplement 1): 125-126, July, 2003

Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARα and PLZF/RARα. Plos One 6(7): E22540-E22540, 2011

The RARa-PLZF oncogenic protein inhibits C/EBPa function in myeloid cells. 2007

The RARa-PLZF fusion protein inhibits C/EBPa function in myeloid cells. Experimental Hematology (Charlottesville) 30(6 Supplement 1): 95, June, 2002

Targeting the acute promyelocytic leukemia-associated fusion proteins PML/RARα and PLZF/RARα with interfering peptides. Plos One 7(11): E48636-E48636, 2013

The tumor suppressor gene DAPK2 is induced by the myeloid transcription factors PU.1 and C/EBPα during granulocytic differentiation but repressed by PML-RARα in APL. Journal of Leukocyte Biology 95(1): 83-93, 2014

Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα-Driven Leukemia. Clinical Cancer Research 21(16): 3685-3694, 2016

MicroRNA-125b-1 accelerates a C-terminal mutant of C/EBPα (C/EBPα-C(m))-induced myeloid leukemia. International Journal of Hematology 96(3): 334-341, 2013

The molecular biology of acute myeloid leukemia. Proto-oncogene expression and function in normal and neoplastic myeloid cells. Clinics in Laboratory Medicine 10(4): 769-796, 1990

TCERG1 inhibits C/EBPα through a mechanism that does not involve sequestration of C/EBPα at pericentromeric heterochromatin. Journal of Cellular Biochemistry 112(9): 2317-2326, 2011

A C-terminal mutant of CCAAT-enhancer-binding protein α (C/EBPα-Cm) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPα-Cm. Experimental Hematology 43(4): 300-8.E1, 2015

Identification of the STAT5B-RARα fusion transcript in an acute promyelocytic leukemia patient without FLT3, NPM1, c-Kit and C/EBPα mutation. European Journal of Haematology 86(5): 442-446, 2011

8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation. Proceedings of the National Academy of Sciences of the United States of America 110(9): 3495-3500, 2013

NLS-RARα promotes proliferation and inhibits differentiation in HL-60 cells. International Journal of Medical Sciences 11(3): 247-254, 2015

The RARalpha-PLZF chimera inhibits C/EBPalpha function and the expression of the G-CSF receptor. Blood 96(11 Part 1): 301a, November 16, 2000