Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:84074-84085. https://doi.org/10.18632/oncotarget.21101

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Abstract

Emiliano Fabiani1,*, Giulia Falconi1,*, Nélida Inés Noguera1,2, Ernestina Saulle3, Laura Cicconi1, Mariadomenica Divona1, Cristina Banella2, Alessandra Picardi1, Anna Maria Cerio4, Letizia Boe5, Massimo Sanchez5, Elvira Pelosi4, Ugo Testa4, Francesco Lo-Coco1,2 and Maria Teresa Voso1

1Università di Roma Tor Vergata, Dipartimento di Biomedicina e Prevenzione, Rome, Italy

2Fondazione Santa Lucia, Laboratorio di Neuro-Oncoematologia, Rome, Italy

3Istituto Superiore di Sanità, Centro Nazionale per la Ricerca e la Valutazione Preclinica e Clinica dei Farmaci, Rome, Italy

4Istituto Superiore di Sanità, Dipartimento di Ematologia ed Oncologia, Rome, Italy

5Istituto Superiore di Sanità, Grandi Strumentazioni e Core Facilities, Rome, Italy

*These authors contributed equally to this work

Correspondence to:

Maria Teresa Voso, email: [email protected]

Keywords: acute promyelocytic leukemia, forkhead box C1, ATRA, decitabine, epigenetic regulation

Received: April 27, 2017     Accepted: August 31, 2017     Published: September 20, 2017

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.


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