Abstract
The arrest of differentiation is a feature of both chronic myelogenous leukemia cells in myeloid blast crisis and myeloid precursors that ectopically express the p210BCR-ABL oncoprotein; however, its underlying mechanisms remain poorly understood. Here we show that expression of BCR-ABL in myeloid precursor cells leads to transcriptional suppression of the granulocyte colony-stimulating factor receptor G-CSF-R (encoded by CSF3R), possibly through down-modulation of C/EBPalpha-the principal regulator of granulocytic differentiation. Expression of C/EBPalpha protein is barely detectable in primary marrow cells taken from individuals affected with chronic myeloid leukemia in blast crisis. In contrast, CEBPA RNA is clearly present. Ectopic expression of C/EBPalpha induces granulocytic differentiation of myeloid precursor cells expressing BCR-ABL. Expression of C/EBPalpha is suppressed at the translational level by interaction of the poly(rC)-binding protein hnRNP E2 with CEBPA mRNA, and ectopic expression of hnRNP E2 in myeloid precursor cells down-regulates both C/EBPalpha and G-CSF-R and leads to rapid cell death on treatment with G-CSF (encoded by CSF3). Our results indicate that BCR-ABL regulates the expression of C/EBPalpha by inducing hnRNP E2-which inhibits the translation of CEBPA mRNA.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / physiology*
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Benzamides
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Blast Crisis / metabolism
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Blast Crisis / pathology
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CCAAT-Enhancer-Binding Protein-alpha / biosynthesis*
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CCAAT-Enhancer-Binding Protein-alpha / genetics
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CCAAT-Enhancer-Binding Proteins
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Carrier Proteins / metabolism
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Cells, Cultured / metabolism
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DNA-Binding Proteins*
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Down-Regulation
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / physiology*
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Gene Expression Regulation*
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Gene Expression Regulation, Leukemic
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Hematopoietic Stem Cells / metabolism
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Heterogeneous-Nuclear Ribonucleoproteins*
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Humans
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Imatinib Mesylate
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Mice
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Myeloid Cells / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Neoplastic Stem Cells / metabolism
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Oligodeoxyribonucleotides / chemistry
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Oligodeoxyribonucleotides / pharmacology
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Piperazines / pharmacology
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Protein Biosynthesis
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Pyrimidines / pharmacology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / isolation & purification
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RNA-Binding Proteins / physiology*
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Receptors, Granulocyte Colony-Stimulating Factor / biosynthesis*
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Receptors, Granulocyte Colony-Stimulating Factor / genetics
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Sequence Alignment
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Sequence Homology, Nucleic Acid
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Transcription Factors*
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Transcription, Genetic
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Transfection
Substances
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Benzamides
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CCAAT-Enhancer-Binding Protein-alpha
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CCAAT-Enhancer-Binding Proteins
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CEBPA protein, human
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Carrier Proteins
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DNA-Binding Proteins
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Heterogeneous-Nuclear Ribonucleoproteins
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Neoplasm Proteins
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Oligodeoxyribonucleotides
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Piperazines
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Protein Isoforms
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Pyrimidines
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RNA, Messenger
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RNA-Binding Proteins
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Receptors, Granulocyte Colony-Stimulating Factor
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Transcription Factors
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Imatinib Mesylate
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Fusion Proteins, bcr-abl