BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2.
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.
Perrotti
Danilo
D
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Danilo.Perrotti@mail.tju.edu
Cesi
Vincenzo
V
Trotta
Rossana
R
Guerzoni
Clara
C
Santilli
Giorgia
G
Campbell
Kenneth
K
Iervolino
Angela
A
Condorelli
Fabrizio
F
Gambacorti-Passerini
Carlo
C
Caligiuri
Michael A
MA
Calabretta
Bruno
B
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001549:Benzamides; D001752:Blast Crisis / Q000378:metabolism / Q000473:pathology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis* / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D005786:Gene Expression Regulation; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection
D001549:Benzamides; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; D010879:Piperazines; D020033:Protein Isoforms; D011743:Pyrimidines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl