BCR-ABL Suppresses C/EBPalpha Expression Through Inhibitory Action of hnRNP E2

Nat Genet. 2002 Jan;30(1):48-58. doi: 10.1038/ng791. Epub 2001 Dec 20.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Benzamides
  • Blast Crisis / metabolism
  • Blast Crisis / pathology
  • CCAAT-Enhancer-Binding Protein-alpha / biosynthesis*
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Proteins
  • Carrier Proteins / metabolism
  • Cells, Cultured / metabolism
  • DNA-Binding Proteins*
  • Down-Regulation
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / physiology*
  • Gene Expression Regulation*
  • Gene Expression Regulation, Leukemic
  • Hematopoietic Stem Cells / metabolism
  • Heterogeneous-Nuclear Ribonucleoproteins*
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Myeloid Cells / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Neoplastic Stem Cells / metabolism
  • Oligodeoxyribonucleotides / chemistry
  • Oligodeoxyribonucleotides / pharmacology
  • Piperazines / pharmacology
  • Protein Biosynthesis
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • Pyrimidines / pharmacology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / isolation & purification
  • RNA-Binding Proteins / physiology*
  • Receptors, Granulocyte Colony-Stimulating Factor / biosynthesis*
  • Receptors, Granulocyte Colony-Stimulating Factor / genetics
  • Sequence Alignment
  • Sequence Homology, Nucleic Acid
  • Transcription Factors*
  • Transcription, Genetic
  • Transfection

Substances

  • Benzamides
  • CCAAT-Enhancer-Binding Protein-alpha
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Neoplasm Proteins
  • Oligodeoxyribonucleotides
  • Piperazines
  • Protein Isoforms
  • Pyrimidines
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Transcription Factors
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl