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Reduced BAP1 activity prevents ASXL1 truncation-driven myeloid malignancy in vivo

Leukemia volume 32, pages 1834–1837 (2018)Cite this article

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Additional sex comb-like 1 (ASXL1) gene encodes the ASXL1 protein, which plays an important role in transcriptional regulation of homeotic gene expression [1]. ASXL1 is frequently mutated in a spectrum of myeloid malignancies, including chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML) [2, 3]. Importantly, these mutations are associated with poor prognosis, suggesting an important role of ASXL1 mutations in disease progression [2,3,4]. Most of ASXL1 mutations are nonsense/frameshift, resulting in truncated forms of the protein lacking the C-terminal PHD finger [2, 5], which are detectable in leukemia cell lines [6]. We and others have shown that Asxl1 loss or transgenic expression of a truncated ASXL1 protein in mice (Asxl1Y588XTg) impaired hematopoietic stem/progenitor cell (HSC/HPC) function and led to diverse myeloid malignancies [7,8,9]. However, the underlying mechanisms remain largely unknown, hindering the development of targeted therapiecs.

ASXL1 exerts its regulatory effects on chromatin through interaction with other protein complexes such as PRC2 [5] and cohesin [10]. ASXL1 is also required for the activity of BAP1 [11,12,13], a deubiquiting (DUB) enzyme regulating homeobox gene expression by controlling the level of H2AK119Ub in opposition to PRC1-mediated gene repression [11, 12]. Recently, Balasubramani et al. [11] reported that ASXL1 truncation mutations confer an enhanced activity on the ASXL1–BAP1 DUB complex [11], highlighting the significance of the ASXL1–BAP1 complex in normal biological processes and cancer progression. We hypothesize that the ASXL1aa1-587 truncation mutant promotes myeloid malignancies by enhancing BAP1 DUB activity.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (CA172408 and CA185751 to F-CY and MX; CA125970 to JWH), National Heart, Lung, and Blood Institute (HL112294 to MX), and Leukemia and Lymphoma Society (F-CY, MX, and SDN). JWH was supported by Research to Prevent Blindness, Inc. Senior Scientific Investigator Award, Melanoma Research Alliance—Melanoma Research Foundation Established Investigator Award, Alcon Research Institute, and a generous gift from Dr. Mark J. Daily. The Bascom Palmer Eye Institute received funding from NIH Core Grant P30EY014801, Department of Defense Grant #W81XWH-13-1-0048, and a Research to Prevent Blindness Unrestricted Grant. We thank the services provided by the Satellite Histological Core of Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine.

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  1. These authors contributed equally: Ying Guo, Hui Yang.

Authors and Affiliations

  1. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Ying Guo, Hui Yang, Shi Chen, Peng Zhang, Rong Li, Stephen D. Nimer, J. William Harbour, Mingjiang Xu & Feng-Chun Yang

  2. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    Ying Guo, Hui Yang, Shi Chen, Peng Zhang, Rong Li, Stephen D. Nimer, J. William Harbour, Mingjiang Xu & Feng-Chun Yang

  3. Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA

    J. William Harbour

  4. Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA

    J. William Harbour

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  1. Ying Guo
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Correspondence to Mingjiang Xu or Feng-Chun Yang.

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Guo, Y., Yang, H., Chen, S. et al. Reduced BAP1 activity prevents ASXL1 truncation-driven myeloid malignancy in vivo. Leukemia 32, 1834–1837 (2018). https://doi.org/10.1038/s41375-018-0126-9

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