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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Research

PML-RAR alpha induces the downmodulation of HHEX: a key event responsible for the induction of an angiogenetic response

Authors: Ernestina Saulle, Alessia Petronelli, Elvira Pelosi, Elena Coppotelli, Luca Pasquini, Ramona Ilari, Francesco Lo-Coco, Ugo Testa

Published in: Journal of Hematology & Oncology | Issue 1/2016

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Abstract

Background

Recent studies indicate that angiogenesis is important in the pathogenesis of acute myeloid leukemias (AMLs). Among the various AMLs, the bone marrow angiogenetic response is particularly pronounced in acute promyelocytic leukemia (APL). However, the molecular mechanisms responsible for this angiogenetic response are largely unknown. In the present study, we have explored the role of HHEX, a homeodomain transcription factor, as a possible mediator of the pro-angiogenetic response observed in APL. This transcription factor seems to represent an ideal candidate for this biologic function because it is targeted by PML-RARα, is capable of interaction with PML and PML-RARα, and acts as a regulator of the angiogenetic response.

Methods

We used various cellular systems of APL, including primary APL cells and leukemic cells engineered to express PML-RARα, to explore the role of the PML-RARα fusion protein on HHEX expression. Molecular and biochemical techniques have been used to investigate the mechanisms through which PML-RARα downmodulates HHEX and the functional consequences of this downmodulation at the level of the expression of various angiogenetic genes, cell proliferation and differentiation.

Results

Our results show that HHEX expression is clearly downmodulated in APL and that this effect is directly mediated by a repressive targeting of the HHEX gene promoter by PML-RARα. Studies carried out in primary APL cells and in a cell line model of APL with inducible PML-RARα expression directly support the view that this fusion protein through HHEX downmodulation stimulates the expression of various genes involved in angiogenesis and inhibits cell differentiation.

Conclusions

Our data suggest that HHEX downmodulation by PML-RARα is a key event during APL pathogenesis.
Appendix
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Metadata
Title
PML-RAR alpha induces the downmodulation of HHEX: a key event responsible for the induction of an angiogenetic response
Authors
Ernestina Saulle
Alessia Petronelli
Elvira Pelosi
Elena Coppotelli
Luca Pasquini
Ramona Ilari
Francesco Lo-Coco
Ugo Testa
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0262-5

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