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The ability of endogenous Nras oncogenes to initiate leukemia is codon-dependent

Leukemia volume 30, pages 1935–1938 (2016)Cite this article

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The mammalian Ras proteins, H-, N- and K-Ras, belong to the small GTPase superfamily. They cycle between a GTP-bound active form and a GDP-bound inactive form.1, 2 The conversion from the GTP-bound form to the GDP-bound form is mediated by the intrinsic GTPase activity of Ras proteins and is greatly accelerated by Ras-associated GAPs (GTPase-activating proteins). Canonical, cancer-associated Ras mutations at codons G12, G13 or Q61 severely compromise the hydrolysis of GTP to GDP, thereby leading to the accumulation of Ras-GTP and hyperactivation of Ras downstream signaling. Mutations in the KRAS and NRAS genes (not in HRAS) are frequently identified in myeloid disorders (15–60%), including acute myeloid leukemia, atypical chronic myeloid leukemia, chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML).3 In these diseases, the frequency of NRAS mutations is significantly higher than that of KRAS mutations.

Although mutations at codons G12, G13 and Q61 of NRAS are all perceived oncogenic equivalents, they display distinct biochemical and functional properties. NRAS G12 and G13 mutations affect the intrinsic GTPase activity of Nras by preventing proper position of the Ras-GAP arginine finger within the catalytic site, whereas Q61 mutations lead to more severe impairment of Nras intrinsic GTPase function.1 Therefore, G12 and G13 mutations are less activating than Q61 mutations. In human cancers with NRAS mutations, G12 mutations are prevalent in myeloid leukemia, whereas Q61 mutations are predominant in plasma cell myeloma and melanoma (Supplementary Figure S1A). In hematopoietic malignancies, ~70% of NRAS G12 mutations are identified in patients with myeloid diseases, but these mutations are rare in those with plasma cell myeloma (Supplementary Figure S1B). In contrast, the incidence of Q61 mutations is equal in patients with myeloid leukemias or plasma cell myeloma (~40% each; Supplementary Figure S1B). Of note, the acquisition of two copies of oncogenic NRAS G12D or G13D alleles is associated with JMML/CMML progression in humans and mice (COSMIC database (http://cancer.sanger.ac.uk/cosmic) and Kong et al.4), indicating that incremental activation of Ras signaling is a pathological mechanism contributing to JMML/CMML development. In a recent study of mutation-specific Nras oncogenicity, only an endogenous Nras Q61R mutation could promote spontaneous melanoma formation in mice.5 However, the ability of endogenous Nras G12D and Q61R mutants to drive leukemogenesis has never been evaluated in a side-by-side comparison.

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Acknowledgements

We thank the University of Wisconsin Carbone Comprehensive Cancer Center (UWCCC) for use of its Shared Services (Flow Cytometry Laboratory and Experimental Pathology Laboratory) to complete this research. This work was supported by R01 grants R01CA152108 and R01HL113066, and a Scholar Award from the Leukemia and Lymphoma Society to JZ. This work was also supported in part by National Institutes of Health/National Cancer Institute P30 CA014520-UWCCC support.

Author contributions

GK and JZ contributed for experimental design, execution as well as writing of this manuscript; Y-IC, XY and YZ for experimental execution; EAR for histopathological analysis and writing of this manuscript; and CEB for generating NrasLSL Q61R/+ allele and writing of this manuscript.

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Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA

    G Kong, Y-I Chang, X You, Y Zhou & J Zhang

  2. Institute of Physiology, National Yang-Ming University, Taipei City, Taiwan

    Y-I Chang

  3. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    E A Ranheim

  4. Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA

    C E Burd

  5. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA

    C E Burd

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  1. G Kong
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Correspondence to J Zhang.

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Kong, G., Chang, YI., You, X. et al. The ability of endogenous Nras oncogenes to initiate leukemia is codon-dependent. Leukemia 30, 1935–1938 (2016). https://doi.org/10.1038/leu.2016.89

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