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Truncated RUNX1 protein generated by a novel t(1;21)(p32;q22) chromosomal translocation impairs the proliferation and differentiation of human hematopoietic progenitors

Oncogene volume 35, pages 125–134 (2016)Cite this article

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Abstract

We have identified a new t(1;21)(p32;q22) chromosomal translocation in a MDS/AML patient that results in expression of an aberrant C-terminally truncated RUNX1 protein lacking several regulatory domains. As similar truncated RUNX1 proteins are generated by genetic aberrations including chromosomal translocations and point mutations, we used the t(1;21)(p32;q22) chromosomal translocation as a model to explore whether C-terminally truncated RUNX1 proteins trigger effects similar to those induced by well-characterized leukemogenic RUNX1 fusion genes. In vitro analysis of transduced human hematopoietic/progenitor stem cells showed that truncated RUNX1 proteins increase proliferation and self-renewal and disrupt the differentiation program by interfering with RUNX1b. These effects are similar to but milder than those induced by the RUNX1/ETO fusion protein. GSEA analysis confirmed similar altered gene expression patterns in the truncated RUNX1 and RUNX1/ETO models, with both models showing alterations in genes involved in self-renewal and leukemogenesis, including homeobox genes, primitive erythroid genes and leukemogenic transcription factors. We propose that C-terminally truncated RUNX1 proteins can contribute to leukemogenesis in a similar way to RUNX1 fusion genes but through a milder phenotype.

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Acknowledgements

This work was supported by an INTRASALUD project PI 12-00425 to JCC. We thank all the coworkers in our laboratory for their excellent technical assistance.

Author Contributions

SR and MCM performed the genetic, cell culture, cytometry and luciferase experiments; SR, JS and FA performed the genomic experiments; RT and JCR designed and performed qRT–PCR experiments, provided the lentiviral vectors and helped with the transduction experiments; EY provided the bone marrow samples and the clinical information; SA provide the clinical assessment and contributed to the discussion; SR and JCC analyzed the data and wrote the manuscript.

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The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre—CNIO, Madrid, Spain

    S Rodriguez-Perales, J Suela, F Acquadro, M C Martin, S Alvarez & J C Cigudosa

  2. Viral Vector Technical Unit, Fundación Centro Nacional de Investigaciones Cardiovascular (CNIC), Madrid, Spain

    R Torres-Ruiz & J C Ramirez

  3. Hematology Service, Hospital Severo Ochoa, Madrid, Spain

    E Yebra

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  1. S Rodriguez-Perales
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Rodriguez-Perales, S., Torres-Ruiz, R., Suela, J. et al. Truncated RUNX1 protein generated by a novel t(1;21)(p32;q22) chromosomal translocation impairs the proliferation and differentiation of human hematopoietic progenitors. Oncogene 35, 125–134 (2016). https://doi.org/10.1038/onc.2015.70

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