TY - JOUR
T1 - The forkhead box C1 (FOXC1) transcription factor is downregulated in acute promyelocytic leukemia
AU - Fabiani, Emiliano
AU - Falconi, Giulia
AU - Noguera, Nélida Inés
AU - Saulle, Ernestina
AU - Cicconi, Laura
AU - Divona, Mariadomenica
AU - Banella, Cristina
AU - Picardi, Alessandra
AU - Cerio, Anna Maria
AU - Boe, Letizia
AU - Sanchez, Massimo
AU - Pelosi, Elvira
AU - Testa, Ugo
AU - Lo-Coco, Francesco
AU - Voso, Maria Teresa
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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 PMLRARA, 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.
AB - 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 PMLRARA, 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.
KW - Acute promyelocytic leukemia
KW - ATRA
KW - Decitabine
KW - Epigenetic regulation
KW - Forkhead box C1
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U2 - 10.18632/oncotarget.21101
DO - 10.18632/oncotarget.21101
M3 - Article
AN - SCOPUS:85030984702
SN - 1949-2553
VL - 8
SP - 84074
EP - 84085
JO - Oncotarget
JF - Oncotarget
IS - 48
ER -