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BCR-ABL suppresses C/EBPα expression through inhibitory action of hnRNP E2

Nature Genetics volume 30, pages 4858 (2002) | Download Citation

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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/EBPα—the principal regulator of granulocytic differentiation. Expression of C/EBPα 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/EBPα induces granulocytic differentiation of myeloid precursor cells expressing BCR-ABL. Expression of C/EBPα 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/EBPα 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/EBPα by inducing hnRNP E2—which inhibits the translation of CEBPA mRNA.

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Acknowledgements

We thank A. Bergamaschi and P. Guaraldi for assistance in hnRNP E2 protein purification and REMSA assays; R. Martinez, D.G. Tenen and H. Radomska for helpful discussion; and A. Leutz for communicating his data on translational control of C/EBPα expression. R.T. is supported by a training grant from the National Institutes of Health. C.G. and G.S. were supported in part by the A. Serra Foundation for Cancer Research. This work was supported in part by grants from the NIH (B.C.), from CALGB (M.A.C.) and from the Associazione Italiana Per La Ricerca sul Cancro (C.G.-P.).

Author information

Author notes

    • Vincenzo Cesi
    •  & Rossana Trotta

    These authors contributed equally to this work.

Affiliations

  1. Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

    • Danilo Perrotti
    • , Vincenzo Cesi
    • , Rossana Trotta
    • , Giorgia Santilli
    • , Kenneth Campbell
    • , Angela Iervolino
    • , Fabrizio Condorelli
    •  & Bruno Calabretta
  2. Department of Biomedical Sciences, Section of General Pathology, University of Modena, Italy.

    • Clara Guerzoni
    •  & Bruno Calabretta
  3. Experimental Oncology, NCI, Milano, 20133 and Hematology Section, S. Gerardo Hospital, Monza, 20052, Italy.

    • Carlo Gambacorti-Passerini
  4. The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

    • Michael A. Caligiuri
  5. The Cancer and Leukemia Group B, Chicago, Illinois, USA.

    • Michael A. Caligiuri

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Correspondence to Danilo Perrotti or Bruno Calabretta.

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DOI

https://doi.org/10.1038/ng791

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