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Acute myeloid leukemia

Insertional mutagenesis identifies cooperation between Setbp1 and Mllt3 in inducing myeloid leukemia development

Leukemia volume 33, pages 2121–2125 (2019)Cite this article

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Multiple cooperating mutations are required to induce transformation during the development of acute myeloid leukemias (AMLs), and identification of these cooperating mutations is essential for developing better combinatorial AML therapies. SETBP1, which encodes an AT-hook transcription factor [1, 2], likely plays a significant role in driving human primary AML development as it was overexpressed in up to 30% of primary AML patients [3, 4], and its overexpression was capable of inducing AML development in mice [5]. Consistent with its association with poor patient prognosis [3, 4], SETBP1 overexpression also likely plays an important role in the maintenance of leukemia-initiating cells (LICs) as it was identified as a top component of a LIC gene expression signature for human AMLs [6]. SETBP1 may control the self-renewal of LICs through direct transcription activation of oncogenes Hoxa9, Hoxa10, and Myb, and repression of tumor suppressor gene Runx1 [1, 5]. SETBP1 may also promote AML development through its interaction and stabilization of oncoprotein SET [3]. Despite the potentially significant contribution by SETBP1 overexpression to the initiation and maintenance of primary human AMLs, its cooperating oncogenic partners in AML development remain unknown.

MLLT3, also known as AF9, first was identified as a fusion partner for MLL1 in human myeloid leukemias [10]. Gene targeting in mice has revealed a critical role of Mllt3 in embryogenesis [11]. MLLT3 later was found to regulate transcriptional elongation as a component of the super elongation complex (SEC) [12]. This function of MLLT3 is likely dependent on its ability to recognize H3K9 acetylation [13]. A role for MLLT3 overexpression in cancer development has not been reported previously.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grant RO1CA143193 (Y.D.) and USUHS Pediatrics Grant QP86GI (Y.D.). The views presented in this paper are those of the authors; no endorsement by the Uniformed Services University of the Health Sciences or the Department of Defense has been given or should be inferred.

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

    Bandana A. Vishwakarma, Kristbjorn O. Gudmundsson, Kevin Oakley, Yufen Han & Yang Du

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Correspondence to Yang Du.

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Vishwakarma, B.A., Gudmundsson, K.O., Oakley, K. et al. Insertional mutagenesis identifies cooperation between Setbp1 and Mllt3 in inducing myeloid leukemia development. Leukemia 33, 2121–2125 (2019). https://doi.org/10.1038/s41375-019-0445-5

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