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  • Original Paper
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Myeloid maturation block by AML1-MTG16 is associated with Csf1r epigenetic downregulation

Oncogene volume 24, pages 5325–5332 (2005)Cite this article

Abstract

De novo epigenetic changes at histone and DNA level that affect gene transcription in cancer may be less random than we originally thought. Leukemia fusion proteins associated with specific chromosome translocations could mechanistically determine the epigenetic fate of specific target genes critical for normal hematopoiesis. This seems to be the case with AML1-MTG16, a fusion protein resulting from the t(16;21) translocation, a hallmark of therapy-related leukemia and myelodysplastic syndrome. Here we show that AML1-MTG16 blocks both myeloid differentiation and proliferation in the 32D/WT1-mouse myeloid cell line. These biological effects can be traced to the AML1 and MTG16 moieties of the fusion protein, respectively. Further, we show that AML1-MTG16 can induce epigenetic repressive changes at the histone and DNA level of the AML1 target gene Csf1r (c-fms), encoding the macrophage colony stimulating factor receptor. We observed that, concomitant with Csf1r downregulation, 32D/WT1 cells lost the ability to undergo myeloid differentiation in response to the granulocyte macrophage colony-stimulating factor (GM-CSF). Thus, there seems to be an association between AML1-MTG16-induced myeloid maturation block and epigenetic changes of a myeloid master gene.

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Acknowledgements

We are indebted to the Department of Clinical Genetics of the Erasmus Medical Center, Rotterdam, for generous hospitality to SR. We thank Violeta Stoyanova and Gert Jan van de Geijn for critical discussions and technical advice. A special thanks to Ms. Ellen Sanders-Noonan for editing this manuscript. This work was partially supported by an AIRC award to NS and a fellowship from the Center of Excellence CISI, University of Milan to SR.

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Authors and Affiliations

  1. Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, 14263, NY, USA

    Stefano Rossetti & Nicoletta Sacchi

  2. Department of Clinical Genetics, Erasmus Medical Center, Dr Molewaterplein 50, 3015GE, Rotterdam, The Netherlands

    Leontine Van Unen & André T Hoogeveen

  3. Department of Hematology, Erasmus Medical Center, 3015GE, Rotterdam, The Netherlands

    Ivo P Touw

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  1. Stefano Rossetti
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  2. Leontine Van Unen
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Correspondence to André T Hoogeveen or Nicoletta Sacchi.

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Rossetti, S., Van Unen, L., Touw, I. et al. Myeloid maturation block by AML1-MTG16 is associated with Csf1r epigenetic downregulation. Oncogene 24, 5325–5332 (2005). https://doi.org/10.1038/sj.onc.1208651

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