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The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros

Oncogene volume 27, pages 2886–2896 (2008)Cite this article

Abstract

The t(10;11)(p13;q14) translocation leads to the fusion of the CALM and AF10 genes. This translocation can be found as the sole cytogenetic abnormality in acute lymphoblastic leukemia, acute myeloid leukemia and in malignant lymphomas. The expression of CALM/AF10 in primary murine bone marrow cells results in the development of an aggressive leukemia in a murine bone marrow transplantation model. Using a yeast two-hybrid screen, we identified the lymphoid regulator Ikaros as an AF10 interacting protein. Interestingly, Ikaros is required for normal development of lymphocytes, and aberrant expression of Ikaros has been found in leukemia. In a murine model, the expression of a dominant negative isoform of Ikaros causes leukemias and lymphomas. The Ikaros interaction domain of AF10 was mapped to the leucine zipper domain of AF10, which is required for malignant transformation both by the CALM/AF10 and the MLL/AF10 fusion proteins. The interaction between AF10 and Ikaros was confirmed by GST pull down and co-immunoprecipitation. Coexpression of CALM/AF10 but not of AF10 alters the subcellular localization of Ikaros in murine fibroblasts. The transcriptional repressor activity of Ikaros is reduced by AF10. These results suggest that CALM/AF10 might interfere with normal Ikaros function, and thereby block lymphoid differentiation in CALM/AF10 positive leukemias.

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Acknowledgements

We thank Pablo Gomez, Katia Georgopoulos and Steven Smale for sending us Ikaros materials. Yihui Lin and Guoliang Xu generously provided AF10 constructs. Brigitte Mack and Manuel Deutsch kindly shared their expertise with the confocal microscope. This project was supported by the German José-Carreras-Leukemia Foundation with a scholarship (F05/06) to Philipp Greif and by a NGFN (Bundesministerium für Bildung und Forschung) grant to SK Bohlander.

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  1. Medizinische Klinik III, Klinikum der LMU München-Großhadern & Klinische Kooperationsgruppe‘Leukämie’ am Hämatologikum der GSF, Munich, Germany

    P A Greif, B Tizazu, A Krause & S K Bohlander

  2. Institut für Molekulare Immunologie, GSF-Forschungszentrum für Umwelt und Gesundheit, Munich, Germany

    E Kremmer

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  1. P A Greif
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Correspondence to S K Bohlander.

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Greif, P., Tizazu, B., Krause, A. et al. The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros. Oncogene 27, 2886–2896 (2008). https://doi.org/10.1038/sj.onc.1210945

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