All-trans retinoic acid combined with 5-Aza-2'-deoxycitidine induces C/EBPα expression and growth inhibition in MLL-AF9-positive leukemic cells.
The present study tested whether all-trans retinoic acid (ATRA) and 5-Aza-2'-deoxycitidine (5-Aza) affect AML cell differentiation and growth in vitro by acting on the CCAAT/enhancer binding protein α (C/EBPα) and c-Myc axis. After exposure to a combination of these agents, cell differentiation and growth arrest were significantly higher in human and murine MLL-AF9-expressing cells than in MLL-AF4/AF5q31-expressing cells, which were partly associated with increased expression of C/EBPα, C/EBPε, and PU.1, and decreased expression of c-Myc. These findings indicate that MLL-AF9-expressing cells are more sensitive to ATRA and 5-Aza, indicating that different MLL fusion proteins possess different epigenetic properties associated with retinoic acid pathway inactivation.
Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Atsushi
A
Fujiki
Toshihiko
T
Imamura
Kenichi
K
Sakamoto
Sachiko
S
Kawashima
Hideki
H
Yoshida
Yoshifumi
Y
Hirashima
Mitsuru
M
Miyachi
Shigeki
S
Yagyu
Takuya
T
Nakatani
Kanji
K
Sugita
Hajime
H
Hosoi
D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000032:analysis / Q000235:genetics; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
D022763:CCAAT-Enhancer-Binding Protein-alpha; C497422:KMT2A protein, human; C489901:MLLT3 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D014212:Tretinoin; D011495:Histone-Lysine N-Methyltransferase; D001374:Azacitidine