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Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

Oncogene volume 26, pages 3352–3363 (2007)Cite this article

Abstract

The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapy-related high-risk acute leukemia. Here, we investigated the biological effects of MLL·AF4, AF4·MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and loss-of-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.

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Acknowledgements

We thank Dr Malek Djabali, INSERM Marseille, for providing and sharing yet unpublished data on the MLLΔSET mouse. We are grateful to Richard Young for providing access to his lab, owing to which his Chip-on-CHIP data were publically available. We thank T Burmeister (Berlin) who provided the cDNAs from adult t(4;11) patients, and André Schrauder (Kiel) who provided the cDNAs from infant t(4;11) patients. This study was supported by grants MA 1876/8-1 from the DFG, N1KR-S12T13 from the BMBF, and 2001.061.2 from the Wilhelm-Sander-Foundation to RM.

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  1. T Wenger

    Present address: Centre d'Immunologie de Marseille-Luminy, Marseille, France

Authors and Affiliations

  1. Institute of Pharmaceutical Biology/ZAFES, JWG-University Frankfurt, Biocenter, Frankfurt/Main, Germany

    A Gaussmann, I Eberle, A Bursen, S Bracharz, T Dingermann & R Marschalek

  2. Department of Surgery, Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany

    T Wenger & I Herr

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  1. A Gaussmann
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Correspondence to R Marschalek.

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

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Gaussmann, A., Wenger, T., Eberle, I. et al. Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation. Oncogene 26, 3352–3363 (2007). https://doi.org/10.1038/sj.onc.1210125

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