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Leukemogenic properties of NUP98-PMX1 are linked to NUP98 and homeodomain sequence functions but not to binding properties of PMX1 to serum response factor

Oncogene volume 27, pages 6056–6067 (2008)Cite this article

Abstract

PMX1 is a member of a non-clustered homeobox gene family, not normally expressed in hematopoietic cells, and first identified for its role in enhancing the binding of the serum response factor (SRF) to the serum responsive element (SRE). PMX1 has never been linked to leukemia on its own, raising the possibility of unique mechanisms underlying the oncogenicity of NUP98-PMX1. To elucidate the leukemogenic potential of NUP98-PMX1, we compared the effects of PMX1 and NUP98-PMX1 and, through strategic mutations, the involvement of the SRE in NUP98-PMX1-mediated leukemia. NUP98-PMX1, but not PMX1, had potent ability to impair differentiation, promote proliferation of myeloid progenitors, induce lethal myeloproliferative disease and to activate a number of genes previously linked to leukemic stem cells. Similar to NUP98-HOX fusions, the transforming potential of NUP98-PMX1 required the NUP98 portion and DNA-binding capability of the PMX1 homeodomain and collaborated with Meis1 to induce more rapid onset myeloproliferative-like myeloid leukemia. The transforming activity of NUP98-PMX1 was independent of its ability to interact with SRF. These findings provide novel evidence of the contributory role of the NUP98 sequence in conferring leukemogenic properties on a partner gene and point to common leukemogenic pathways for NUP98-PMX1 and NUP98-clustered HOX fusions.

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Acknowledgements

This work was supported by the Terry Fox Foundation of Canada and by the Canadian Institutes of Health for Research. KH and BA were recipients of fellowships from the Leukemia and Lymphoma Society of Canada. We thank Drs Florian Kuchenbauer and Eric Yung for technical assistance.

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Authors and Affiliations

  1. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    K Hirose, C Abramovich, B Argiropoulos & R K Humphries

  2. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    R K Humphries

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  1. K Hirose
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  2. C Abramovich
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  3. B Argiropoulos
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  4. R K Humphries
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Correspondence to R K Humphries.

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

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Hirose, K., Abramovich, C., Argiropoulos, B. et al. Leukemogenic properties of NUP98-PMX1 are linked to NUP98 and homeodomain sequence functions but not to binding properties of PMX1 to serum response factor. Oncogene 27, 6056–6067 (2008). https://doi.org/10.1038/onc.2008.210

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