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Sustained leukaemic phenotype after inactivation of BCR-ABLp190 in mice

Oncogene volume 26, pages 1702–1713 (2007)Cite this article

Abstract

Pharmacological inactivation of cancer genes or products is being used as a strategy for therapy in oncology. To investigate the potential role of BCR-ABLp190 cessation in leukaemia development, we generated mice carrying a tetracycline-repressible BCR-ABLp190 transgene. These mice were morphologically normal at birth, and developed leukaemias. Disease was characterized by the presence of B-cell blasts co-expressing myeloid markers, reminiscent of the human counterpart. BCR-ABLp190 activation can initiate leukaemia in both young and adult mice. Transitory expression of BCR-ABLp190 is enough to develop leukaemia. Suppression of the BCR-ABLp190 transgene in leukaemic CombitTA-p190 mice did not rescue the malignant phenotype, indicating that BCR-ABLp190 is not required to maintain the disease in mice. Similar results were obtained by inactivation of BCR-ABLp190 with STI571 (Gleevec; Novartis, East Hanover, NJ, USA) in leukaemic CombitTA-p190 mice. However, gradual suppression of BCR-ABLp190 in leukaemic CombitTA-p190 mice identified a minimum level of BCR-ABLp190 expression necessary to revert the specific block in B-cell differentiation in the leukaemic cells. Overall, the findings indicate that BCR-ABLp190 appears to cause epigenetic and/or genetic changes in tumour-maintaining cells that render them insensitive to BCR-ABLp190 inactivation.

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Acknowledgements

We thank all members of lab 13 at IBMCC for their helpful comments and constructive discussions on this project. Research in our group is supported partially by FEDER and by MEC (SAF2003-01103, and PETRI No. 95-0913.OP), Junta de Castilla y León (CSI03A05), FIS (PI050087, PI050116, G03/179 and G03/136), Fundación de Investigación MMA, Federación de Cajas de Ahorro Castilla y León (I Convocatoria de Ayudas para Proyectos de Investigación Biosanitaria con Células Madre) and CDTEAM project. MPC is a postdoctoral fellow supported by G03/136 and G03/179 networks. MSM research is supported by FIS grant no PI041271.

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  1. M Pérez-Caro and N Gutierrez-Cianca: These authors have contributed equally to this work.

Authors and Affiliations

  1. Laboratorio 13, Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC/Universidad de Salamanca, Campus Unamuno, Salamanca, Spain

    M Pérez-Caro, N Gutierrez-Cianca, I González-Herrero, I López-Hernández & I Sánchez-García

  2. Servicio de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain

    T Flores

  3. Servicio de Citometría, Universidad de Salamanca, Salamanca, Spain

    A Orfao

  4. Department of Medicine, Universidad de Salamanca, Salamanca, Spain

    M Sánchez-Martín

  5. Area de Reproducción Animal, Centro de Investigación y Tecnología, Madrid, Spain

    A Gutiérrez-Adán & B Pintado

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  1. M Pérez-Caro
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Correspondence to I Sánchez-García.

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Pérez-Caro, M., Gutierrez-Cianca, N., González-Herrero, I. et al. Sustained leukaemic phenotype after inactivation of BCR-ABLp190 in mice. Oncogene 26, 1702–1713 (2007). https://doi.org/10.1038/sj.onc.1209968

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