Absence of the transcription factor CCAAT enhancer binding protein alpha results in loss of myeloid identity in bcr/abl-induced malignancy.
The lineage-determining transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is required for myeloid differentiation. Decreased function or expression of C/EBPalpha is often found in human acute myeloid leukemia. However, the precise impact of C/EBPalpha deficiency on the maturation arrest in leukemogenesis is not well understood. To address this question, we used a murine transplantation model of a bcr/abl-induced myeloproliferative disease. The expression of bcr/abl in C/EBPalphapos fetal liver cells led to a chronic myeloid leukemia-like disease. Surprisingly, bcr/abl-expressing C/EBPalpha-/- fetal liver cells failed to induce a myeloid disease in transplanted mice, but caused a fatal, transplantable erythroleukemia instead. Accordingly, increased expression of the transcription factors SCL and GATA-1 in hematopoietic precursor cells of C/EBPalpha-/-R01-EY-11298 ) fetal livers was found. The mechanism for the lineage shift from myeloid to erythroid leukemia was studied in a bcr/abl-positive cell line. Consistent with findings of the transplant model, expression of C/EBPalpha and GATA-1 was inversely correlated. Id1, an inhibitor of erythroid differentiation, was identified as a critical direct target of C/EBPalpha. Down-regulation of Id1 by RNA interference impaired C/EBPalpha-induced granulocytic differentiation. Taken together, our study provides evidence that myeloid lineage identity of malignant hematopoietic progenitor cells requires the residual expression of C/EBPalpha.
Wagner
Katharina
K
Harvard Institutes of Medicine, Room 954, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Zhang
Pu
P
Rosenbauer
Frank
F
Drescher
Bettina
B
Kobayashi
Susumu
S
Radomska
Hanna S
HS
Kutok
Jeffery L
JL
Gilliland
D Gary
DG
Krauter
Jürgen
J
Tenen
Daniel G
DG
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000172:deficiency* / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000473:pathology; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D051792:Basic Helix-Loop-Helix Proteins; D022763:CCAAT-Enhancer-Binding Protein-alpha; D016044:Fusion Proteins, bcr-abl; D050982:GATA1 Transcription Factor; D051798:Inhibitor of Differentiation Protein 1; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C494689:Gata1 protein, mouse; C489366:Tal1 protein, mouse