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

Nature Genetics volume 30, pages 48–58 (2002)Cite this article

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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Figure 1: Effects of BCR-ABL on G-CSF-R expression.
Figure 2: Functional relationship between BCR-ABL and expression of C/EBPα.
Figure 3: Proteasome-dependent degradation and neo-synthesis of C/EBPα in parental and BCR-ABL–expressing cells.
Figure 4: BCR-ABL–induced suppression of CEBPA mRNA translation depends on the integrity of its intercistronic region.
Figure 5: Characterization of intercistronic CEBPA mRNA-binding proteins.
Figure 6: Levels of hnRNP E2 in BCR-ABL–expressing cells.
Figure 7: In vivo and in vitro effects of hnRNP E2 on expression of C/EBPα.

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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.).

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Author notes

  1. Vincenzo Cesi and Rossana Trotta: These authors contributed equally to this work.

Authors and Affiliations

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

    Carlo Gambacorti-Passerini

  4. Hematology Section, S. Gerardo Hospital, Monza, 20052, Italy

    Carlo Gambacorti-Passerini

  5. The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio

    Michael A. Caligiuri

  6. The Cancer and Leukemia Group B, Illinois, Chicago, USA

    Michael A. Caligiuri

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Correspondence to Danilo Perrotti or Bruno Calabretta.

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Perrotti, D., Cesi, V., Trotta, R. et al. BCR-ABL suppresses C/EBPα expression through inhibitory action of hnRNP E2. Nat Genet 30, 48–58 (2002). https://doi.org/10.1038/ng791

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