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The hDMP1 tumor suppressor is a new WT1 target in myeloid leukemias

Leukemia volume 22, pages 1087–1090 (2008)Cite this article

The Wilms' tumor gene WT1 is expressed only in hematopoietic progenitor cells and not in mature blood cells. In accordance, high levels of WT1 are found in acute myeloid leukemia blast cells, a cell type characterized by an immature phenotype.1 The expression of the WT1 transcription factor in leukemic cells is proposed to exert an antiapoptotic effect. Investigation of the mechanisms by which WT1 regulates apoptosis has revealed that several bcl-2 family members are induced by WT1, including bcl-2 itself, the proapoptotic family members Bak and Bax, and the anti-apoptotic family member Bfl-1/A1. Nevertheless, there are conflicting reports whether bcl-2 is the main WT1 target in an antiapoptotic phenotype. The transcription factor human cyclin-dependent myb-like protein 1 (hDMP1, hDMTF1), a critical and positive regulator of the ARF tumor suppressor, is highly expressed in terminally differentiated cells. Given the differentiation block seen in acute myeloid leukemia, we were asking if DMP1 might be a new WT1-repressed transcriptional target.

To evaluate whether WT1 represses hDMP1 transcription, in the absence of differentiation, we ectopically expressed WT1 in WT1- negative U937 leukemic cells.5 Expression of WT1 led to a 50% decrease in hDMP1 transcript levels. Moreover, expression of WT1 in these cells markedly inhibited induction of hDMP1 upon ATRA or PMA treatment. The induction of hDMP1 in parental U937 cells was 6.3- and 4-fold, whereas in U937-WT1 hDMP1 induction was only 1.9- and 1.4-fold (Figure 1d).

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Acknowledgements

We thank A Britschgi for assistance in ChIP assays. This work was supported by grants from the Bernese Cancer League (to MPT), the Swiss National Foundation 3100A0-112385 (to AT and MFF) the Marlies-Schwegler Foundation and the Bernese Foundation of Cancer Research (to MFF and AT) the Werner and Hedy Berger-Janser Foundation of Cancer Research (to MFF and MPT), the National Institutes of Health DK49886 and AI49165 (to BET) and the Swedish Cancer Foundation (to UG). MPT, UG, BET, MFF and AT participated in designing the research and wrote the paper; MPT, UG and DS performed the research. All authors checked the final version of the manuscript.

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Authors and Affiliations

  1. Department of Clinical Research, Experimental Oncology/Hematology, University of Berne, Berne, Switzerland

    M P Tschan, D Shan, M F Fey & A Tobler

  2. Department of Hematology, Lund University, Lund, Sweden

    U Gullberg

  3. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA

    B E Torbett

  4. Department of Medical Oncology, University Hospital Inselspital, Berne, Switzerland

    M F Fey

  5. Department of Hematology, University Hospital Inselspital, Berne, Switzerland

    A Tobler

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  1. M P Tschan
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Correspondence to M P Tschan.

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Tschan, M., Gullberg, U., Shan, D. et al. The hDMP1 tumor suppressor is a new WT1 target in myeloid leukemias. Leukemia 22, 1087–1090 (2008). https://doi.org/10.1038/sj.leu.2405018

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