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Expression of CCL9/MIP-1γ is repressed by BCR/ABL and its restoration suppresses in vivo leukemogenesis of 32D-BCR/ABL cells

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Abstract

Transformation of hematopoietic cells by the BCR/ABL oncogene is caused by perturbation of signal transduction pathways leading to altered patterns of gene expression and activity. By oligonucleotide microarray hybridization of polysomal RNA of untreated and STI571-treated 32D-BCR/ABL cells, we identified the β-chemokine CCL9 as a gene regulated by BCR/ABL in a tyrosine kinase-dependent manner. BCR/ABL repressed CCL9 expression at the transcriptional level by mechanisms involving suppression of p38 MAP kinase, and modulation of the activity of CDP/cut and C/EBPα, two transcription regulators of myeloid differentiation. However, repression of C/EBP-dependent transcription did not prevent the induction of CCL9 expression by STI571, suggesting that C/EBPα is involved in maintaining rather than in inducing CCL9 expression. Restoration of CCL9 expression in 32D-BCR/ABL cells had no effect on the in vitro proliferation of these cells, but reduced their leukemogenic potential in vivo, possibly by recruitment of CD3-positive immune cells. Together, these findings suggest that downregulation of chemokine expression may be involved in BCR/ABL-dependent leukemogenesis by altering the relationship between transformed cells and the microenvironment.

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Acknowledgements

We thank Cathy Tomastik for editorial assistance, A Pierce (Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester, UK) for the kind gift of FDCP-mix BCR/ABL cells and A Mondino (S Raffaele Scientific Institute, Milano, Italy) for insightful discussion. Giorgio Iotti was supported, in part, by a fellowship of the Fondazione Cassa di Risparmio di Carpi. Maria Rosa Lidonnici was supported, in part, by a fellowship of the American-Italian Foundation for Cancer Research. Francesca Corradini was supported, in part, by a fellowship of the Associazione Italiana Ricerca sul Cancro (AIRC). This work was supported, in part, by NIH Grant PO178890 to B Calabretta. This work is dedicated to the memory of Dr Bice Perussia

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA, USA

    G Iotti, G Ferrari-Amorotti, M R Lidonnici, M Ronchetti, M Bardini & B Calabretta

  2. Department of Biomedical Sciences, Universitá di Modena e Reggio Emilia, Modena, Italy

    G Iotti, C Rosafio & F Corradini

  3. IFOM, FIRC Institute of Molecular Oncology, Milano, Italy

    G Iotti & F Blasi

  4. Wyeth Genetics Institute, Cambridge, MA, USA

    Y Zhang & R Martinez

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  1. G Iotti
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Correspondence to B Calabretta.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Iotti, G., Ferrari-Amorotti, G., Rosafio, C. et al. Expression of CCL9/MIP-1γ is repressed by BCR/ABL and its restoration suppresses in vivo leukemogenesis of 32D-BCR/ABL cells. Oncogene 26, 3482–3491 (2007). https://doi.org/10.1038/sj.onc.1210146

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