Desferrioxamine induces leukemic cell differentiation potentially by hypoxia-inducible factor-1 alpha that augments transcriptional activity of CCAAT/enhancer-binding protein-alpha.
We reported recently that cobalt chloride-simulated hypoxia and mild hypoxia modified the differentiation of human acute myeloid leukemic (AML) cells, probably acting via a hypoxia-inducible factor-1 alpha (HIF-1 alpha)-dependent mechanism. In this study, we investigated the effect of desferrioxamine (DFO), an iron chelator with 'hypoxia-mimetic' activity, on the differentiation of AML cells. The results showed that DFO at nontoxic concentrations induced the differentiation of AML cell lines NB4 and U937, as assessed by morphological criteria and differentiation-associated antigens. DFO-induced differentiation parallel to the rapid accumulation of HIF-1 alpha protein in these two cell lines. Of importance, the transient transfection of HIF-1 alpha cDNA induced U937 cells to develop the differentiation-related alterations such as growth arrest and increased CD11b expression. Furthermore, the inducible expression of chromosome translocation t(8;21)-generated leukemogenic AML1-ETO fusion gene attenuated DFO-induced differentiation of U937 cells with the decrease of CCAAT/enhancer-binding protein alpha (C/EBP alpha), a critical factor for granulocytic differentiation. Using immunoprecipitation and luciferase reporter assay, HIF-1 alpha was also shown to interact physically with and to increase the transcriptional activity of C/EBP alpha. Taken together, these results provided novel evidence for a role of HIF-1 alpha in AML cell differentiation, and suggested that C/EBP alpha might be a downstream effector for HIF-1 alpha-mediated differentiation.
Jiang
Y
Y
Department of Pathophysiology, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University (SSMU), Shanghai, China.
Xue
Z-H
ZH
Shen
W-Z
WZ
Du
K-M
KM
Yan
H
H
Yu
Y
Y
Peng
Z-G
ZG
Song
M-G
MG
Tong
J-H
JH
Chen
Z
Z
Huang
Y
Y
Lübbert
M
M
Chen
G-Q
GQ
D000208:Acute Disease; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D003676:Deferoxamine / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C107844:AML1-ETO fusion protein, human; D022763:CCAAT-Enhancer-Binding Protein-alpha; D050676:Core Binding Factor Alpha 2 Subunit; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; D003676:Deferoxamine