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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases

Leukemia volume 22, pages 2208–2216 (2008)Cite this article

Abstract

The NUP214-ABL1 fusion kinase has recently been identified in 6% of patients with T-cell acute lymphoblastic leukemia. In contrast to the more common oncogenic ABL1 fusion BCR-ABL1, NUP214-ABL1 localizes to the nuclear pore complexes and has attenuated transforming properties in hematopoietic cells and in mouse bone marrow transplant models. We have performed a thorough biochemical comparative analysis of NUP214-ABL1 and BCR-ABL1 and show that, despite their common tyrosine kinase domain, the two fusion proteins differ in many critical catalytic properties. NUP214-ABL1 has lower in vitro tyrosine kinase activity, which is in agreement with the absence of phosphorylation on its activation loop. NUP214-ABL1 was more sensitive to imatinib (Glivec) than BCR-ABL1 in vitro and in cells, indicating a different activation state and conformation of the two ABL1 fusion kinases. Using a peptide array, we identified differences in the spectrum and efficiency of substrate peptide phosphorylation and a differential involvement of Src kinases in downstream signaling. These results clearly indicate that different fusion partners of the same kinase can determine not only localization, but also critical functional properties of the enzyme such as inhibitor sensitivity and substrate preference, with subsequent differences in downstream signaling effectors and likely consequences in disease pathogenesis.

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Acknowledgements

We thank Ines Kaupe for expert technical assistance, Tilmann Buerckstuemmer, Christoph Baumann and Florian Grebien for the critical reading of the manuscript and all members of the Cools and Superti-Furga lab for help and discussions. KDK is an ‘Aspirant’ researcher of the FWO-Vlaanderen. This work was supported by the Austrian Academy of Sciences, the FWF (Grant no. P18737-B11), AICR, EACR and Research Grant of the Fund for Scientific Research—Flanders (Belgium).

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Authors and Affiliations

  1. Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium

    K De Keersmaecker & J Cools

  2. Center for Human Genetics, Leuven, Belgium

    K De Keersmaecker & J Cools

  3. Ortho Biotech Oncology Research and Development, Beerse, Belgium

    M Versele

  4. Directors Group, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    G Superti-Furga & O Hantschel

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  1. K De Keersmaecker
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Correspondence to O Hantschel.

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

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De Keersmaecker, K., Versele, M., Cools, J. et al. Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases. Leukemia 22, 2208–2216 (2008). https://doi.org/10.1038/leu.2008.242

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