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Acute myeloid leukemia

Interaction with XPO1 is essential for SETBP1 to induce myeloid transformation

Leukemia volume 33, pages 2758–2762 (2019)Cite this article

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SETBP1, which encodes a large AT-hook transcription factor of over 1500 amino acids, was first cloned in a screen to identify interacting factors for oncoprotein SET [1]. Its abnormal activation due to overexpression or missense mutations has recently been found to occur frequently in a variety of human myeloid malignancies, including primary acute myeloid leukemias (AMLs) [2], chronic myeloid leukemia blast crisis (CML-BC) [3], atypical chronic myeloid leukemia [4], chronic myelomonocytic leukemia (CMML) [5], secondary AML [5], juvenile myelomonocytic leukemia (JMML) [6], and myelodysplastic syndrome (MDS) [7, 8]. SETBP1 activation likely plays an important role in driving transformation in these diseases as overexpression of either wild-type Setbp1 or its missense mutants has been shown to induce AML development in mice. SETBP1 activation has also been associated with poor prognosis in many of these malignancies [2, 4, 5], suggesting a urgent need for developing targeted therapies against SETBP1. Targeting SETBP1-induced transcriptional activation may represent a promising therapeutic strategy since transcriptional activation of Hoxa9, Hoxa10, and Myb by Setbp1 has been found to be crucial for Setbp1-induced transformation [3, 9]. However, the molecular mechanisms responsible for such transcriptional activation remain unknown as critical interacting partners for Setbp1 in activating transcription in myeloid progenitors have yet to be identified.

Although Xpo1 is known for its role in nuclear exportation, some recent studies have suggested that it may also function as a transcriptional regulator by binding to chromatin [13, 14]. To start testing the possibility that Xpo1 may be a cofactor for Setbp1 and Setbp1(D/N) in transcriptional regulation, we carried out chromatin immunoprecipitation (ChIP) studies in myeloid progenitor cells immortalized by the expression of 3xFLAG-tagged Setbp1 or Setbp1(D/N) using an Xpo1-specific antibody. Regions of the Hoxa9 promoter were readily detected in the precipitates prepared by the Xpo1 antibody, similarly to the precipitates generated by anti-FLAG M2 antibody (Fig. 1c and Supplementary Fig. 2), supporting the notion that Xpo1 cooperates with Setbp1 and Setbp1(D/N) to directly regulate the transcription of Setbp1 target genes.

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Acknowledgements

This work was supported by Murtha Cancer Center grant HU0001-14-1-0010 (Y.D.) and Uniformed Services University of the Health Sciences (USUHS) Pediatrics grant QP86GI (Y.D.). The views presented in this manuscript are those of the authors; no endorsement by USUHS or the Department of Defense has been given or should be inferred.

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  1. Gary Crouch

    Present address: Division of Pediatric Hematology/Oncology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Authors and Affiliations

  1. Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Nhu Nguyen, Kevin Oakley, Yufen Han, Gary Crouch & Yang Du

  2. Hematology-Oncology Service, Walter Reed National Military Medical Center, Bethesda, MD, USA

    Mary Kwok

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Nguyen, N., Oakley, K., Han, Y. et al. Interaction with XPO1 is essential for SETBP1 to induce myeloid transformation. Leukemia 33, 2758–2762 (2019). https://doi.org/10.1038/s41375-019-0521-x

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