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

// Emiliano Fabiani 1, * , Giulia Falconi 1, * , Nelida Ines Noguera 1, 2 , Ernestina Saulle 3 , Laura Cicconi 1 , Mariadomenica Divona 1 , Cristina Banella 2 , Alessandra Picardi 1 , Anna Maria Cerio 4 , Letizia Boe 5 , Massimo Sanchez 5 , Elvira Pelosi 4 , Ugo Testa 4 , Francesco Lo-Coco 1, 2 and Maria Teresa Voso 1 1 Universita di Roma Tor Vergata, Dipartimento di Biomedicina e Prevenzione, Rome, Italy 2 Fondazione Santa Lucia, Laboratorio di Neuro-Oncoematologia, Rome, Italy 3 Istituto Superiore di Sanita, Centro Nazionale per la Ricerca e la Valutazione Preclinica e Clinica dei Farmaci, Rome, Italy 4 Istituto Superiore di Sanita, Dipartimento di Ematologia ed Oncologia, Rome, Italy 5 Istituto Superiore di Sanita, Grandi Strumentazioni e Core Facilities, Rome, Italy * These authors contributed equally to this work Correspondence to: Maria Teresa Voso, email: voso@med.uniroma2.it 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.