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Role of Setbp1 in Myeloid Leukemia Development

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Technical Report

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Uniformed Services University of the Health Sciences Bethesda United States

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SETBP1, an AT-hook transcription factor, was first identified through its interaction with SET. Since then it has been implicated in development of myeloid leukemias either through overexpression or missense mutation. We have found previously that overexpression of Setbp1 can immortalize mouse myeloid progenitors in culture through activation of Homeobox genes, Hoxa9 and Hoxa10 both in vitro and in vivo. However, it is not known whether activation of Setbp1 alone is sufficient to induce myeloid leukemia development. Here we show that Setbp1 overexpression in murine bone marrow progenitors through retroviral transduction is capable of inducing myeloid leukemia development in irradiated recipient mice. In pre-leukemia stage, overexpression of Setbp1 enhances the self-renewal of hematopoietic stem cells HSCs and expands granulocyte macrophage progenitors GMPs. Interestingly, Setbp1 activation also causes transcriptional repression of tumor suppressor gene Runx1 and this effect is crucial for Setbp1-induced transformation. Runx1 repression is induced by Setbp1-mediatedrecruitment of Hdac1 to Runx1 promoters and can be relieved by treatment with histone deacetylases HDAC inhibitors entinostat and vorinostat. Moreover, treatment with these inhibitors caused efficient differentiation of Setbp1-induced myeloid leukemia cells and immortalized myeloid progenitors in culture and significantly extended the survival of mice with Setbp1-induced myeloid neoplasm, suggesting that HDAC inhibition could be an effective strategy for treating myeloid malignancies with SETBP1 activation. Previous observations demonstrated that overexpression of Setbp1 in mouse bone marrow cells is capable of inducing myeloid leukemia development in mice. However, only 50 of the mice receiving Setbp1-transduced cells developed leukemia in 10 months, suggesting that additional cooperating mutations may be required for Setbp1-induced leukemia development.

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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