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Animal models

Knockout of the RAS endoprotease RCE1 accelerates myeloid leukemia by downregulating GADD45b

Leukemia volume 35, pages 606–609 (2021)Cite this article

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Hyperactive RAS signaling causes hematological malignancies including acute, chronic, and juvenile forms of myeloid leukemia [1]. The RAS proteins are targeted to the plasma membrane following posttranslational processing of a carboxyl-terminal CAAX motif [2]. RAS converting enzyme 1 (RCE1) is responsible for one of these processing steps: the endoproteolytic cleavage of the last three amino acids (i.e., the –AAX) following farnesyl-lipidation of the cysteine residue (i.e., the “C” in CAAX) [3].

Knockout of Rce1 in mouse cells mislocalizes RAS away from the plasma membrane and reduces oncogenic RAS transformation in fibroblasts and skin carcinoma cells in vitro, suggesting that targeting RCE1 might be useful as an anticancer therapeutic strategy [4, 5]. Surprisingly however, Rce1 knockout in myeloid cells transforms a progressive KRAS-induced myeloproliferative neoplasm (MPN) into an acute myeloid leukemia [6]. Indeed, although KRAS is mislocalized, the absence of Rce1 markedly increases white blood cell counts, the percentage of immature cells in blood, and spleen and liver weights; and reduces hemoglobin levels and causes the mice to die more rapidly [6].

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Fig. 1: Knockout of Rce1 accelerates KRASG12D-induced MPN by reducing Gadd45b expression.

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Acknowledgements

We thank Dr. Luis Parada for the Nf1fl/fl mice. This study was supported by grants from the Knut and Alice Wallenberg Foundation; the Swedish Cancer Society; the Swedish Children’s Cancer Fund; the Swedish Research Council; the Sjöberg Foundation; StratCan; Center for Innovative Medicine (to MOB); Gothenburg Medical Society (to CK); and The Swedish Society for Medical Research, the Swedish Medical Research Council, and the Wallenberg Center for Molecular and Translational Medicine (to VIS).

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Authors and Affiliations

  1. Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30, Gothenburg, Sweden

    Christin Karlsson, Murali K. Akula, Anna Staffas, Jaroslaw Cisowski, Volkan I. Sayin, Mohamed X. Ibrahim & Martin O. Bergo

  2. Institute of Biomedicine, University of Gothenburg, SE-405 30, Gothenburg, Sweden

    Christin Karlsson & Anna Staffas

  3. Institute of Medicine, University of Gothenburg, SE-405 30, Gothenburg, Sweden

    Murali K. Akula & Jaroslaw Cisowski

  4. Department of Surgery, Institute of Clinical Sciences, Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, SE-405 30, Gothenburg, Sweden

    Volkan I. Sayin

  5. Institute of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden

    Mohamed X. Ibrahim & Martin O. Bergo

  6. Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30, Gothenburg, Sweden

    Per Lindahl

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  1. Christin Karlsson
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  8. Martin O. Bergo
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Contributions

CK designed the study, performed experiments, interpreted data, made figures and statistics, and wrote the first draft of the manuscript; MK designed and performed experiments; AS designed and performed experiments; JC designed and performed experiments; VIS designed experiments and provided reagents and funding; MXI designed experiments, interpreted data, and made figures; PL designed the study, interpreted data, and made figures; and MOB conceived the study, provided funding, and wrote the manuscript. All authors proofread and approved the final version of the manuscript.

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Correspondence to Martin O. Bergo.

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Karlsson, C., Akula, M.K., Staffas, A. et al. Knockout of the RAS endoprotease RCE1 accelerates myeloid leukemia by downregulating GADD45b. Leukemia 35, 606–609 (2021). https://doi.org/10.1038/s41375-020-0859-0

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