The forkhead box C1 (FOXC1) transcription factor is downregulated in acute promyelocytic leukemia.

Emiliano Fabiani,Ugo Testa,Laura Cicconi,Letizia Boe,Elvira Pelosi,Anna Maria Cerio,Maria Teresa Voso,Nélida Inés Noguera,Francesco Lo-Coco,Cristina Banella,Mariadomenica Divona,Giulia Falconi,Ernestina Saulle,Massimo Sanchez,Alessandra Picardi

doi:10.18632/oncotarget.21101

Emiliano Fabiani, Ugo Testa + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.21101

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Abstract

Forkhead box (FOX) genes encode transcription factors, which regulate embryogenesis and play an important role in hematopoietic differentiation and in mesenchymal niche maintenance. Overexpression of the family member FOXC1 has been reported in solid tumors and acute myeloid leukemia (AML).We studied FOXC1 expression and function in acute promyelocytic leukemia (APL) and normal hematopoietic progenitors. FOXC1 mRNA and protein levels were significantly lower in primary marrow samples from 27 APL patients, as compared to samples obtained from 27 patients with other AML subtypes, and 5 normal CD34+ hematopoietic cells. FOXC1 expression significantly increased in APL samples at the time of remission following consolidation treatment. In cell lines overexpressing PML-RARA, and in the NB4 t(15;17)-positive cell line, FOXC1 expression was lower than in other non-APL cell lines, and increased following treatment with all-trans retinoic acid (ATRA), due to functional binding of ATRA to the FOXC1 promoter region. Reduced FOXC1 expression was also associated to DNA hypermethylation of the +354 to +568 FOXC1 region, both in primary APL, and in NB4 cells. Treatment of NB4 cells with decitabine demethylated FOXC1 and upregulated its expression.Our findings indicate that FOXC1 is consistently repressed in APL due to hypermethylation and the presence of the PML-RARA rearrangement. A potential role of hypomethylating treatment in advanced APL remains to be established.

Highlights

Acute promyelocytic leukemia (APL) is a welldefined type of acute myeloid leukemia (AML), characterized by the balanced t(15,17) chromosomal translocation, resulting in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor-α (RARA)genes
BM (n = 3) expressed FOXC1 at levels similar to those observed in AML, but significantly higher than those detected in acute promyelocytic leukemia (APL) (p = 0.0061, Figure 1A)
Since APL is characterized by a maturation block at the promyelocyte stage, removed by all-trans retinoic acid (ATRA), we investigated the kinetics of FOXC1 expression during the early phases of normal granulocytic differentiation, using an in vitro differentiation model starting from CD34+ cells

Summary

Introduction

The aberrant oncogenic protein PML-RARA blocks myeloid differentiation at the promyelocyte stage by exerting dominant negative effects on wildtype RARA and PML genes, through transcriptional and post-transcriptional mechanisms. PML-RARA constitutively represses RA-target genes by recruiting chromatin remodelling proteins such as www.impactjournals.com/oncotarget. The differentiation block is further accomplished by binding to RA-response elements in the promoter region of myeloid transcription factor PU., the tumor suppressor PTEN, and stimulating transcription of pro-leukemogenic genes driven by hypoxia-induced factors (HIFs) [2,3,4]. In melanoma cells and tissues, the promoter region of the family member FOXC1 is hypomethylated compared to normal tissues and this leads to upregulation of its expression [12]. Hypomethylating treatment of the M219 and M15 melanoma cell lines upregulated FOXC1 protein expression [12]

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