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Inactivating GGTase-I reduces disease phenotypes in a mouse model of K-RAS-induced myeloproliferative disease

Leukemia volume 25, pages 186–189 (2011)Cite this article

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Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the prenylation of several proteins, such as the RHO family proteins, that contribute to tumor development and metastasis. Inhibiting GGTase-I, to interfere with the activity of the RHO family proteins, has been viewed as a potential strategy for cancer therapy. Several inhibitors against GGTase-I have been developed and a clinical trial is ongoing.1 However, the efficacy and toxicity among different GGTase-I inhibitors have varied widely, which have made it difficult to distinguish mechanism-related effects from off-target effects.2, 3 The rationale for targeting GGTase-I was supported by genetic studies in mice: inactivating Pggt1b, the gene encoding GGTase-I, reduced tumor development and improved survival in mice with K-RAS-induced lung cancer.4 Nothing is yet known about the impact of inhibiting GGTase-I on the development of hematologic malignancies.

PCR analysis of genomic DNA of Pggt1bfl/+KM and Pggt1bfl/ΔKM fetal liver cells showed that Cre expression and the Kras2LSL allele had not been activated by endogenous interferon in utero (Figure 1b). In mice transplanted with Pggt1bfl/+KM cells, pI-pC injection activated the Kras2G12D allele and inactivated one Pggt1b allele, as judged by PCR of genomic DNA from blood (Figure 1b). In mice transplanted with Pggt1bfl/ΔKM cells, pI-pC injection activated the Kras2G12D allele and resulted in inactivation of both copies of Pggt1b (Figure 1b). The inactivation of Pggt1b resulted in accumulation of nonprenylated RAP1A (a marker for absent GGTase-I activity) as judged by western blots of protein extracts of bone marrow cells from mice transplanted with Pggt1bfl/ΔKM cells (Figure 1c).

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Acknowledgements

This study was supported by grants from the European Research Council, the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Children's Cancer Foundation and by local ALF funds (to MOB). MOB is a research fellow of the Swedish Medical Research Council. We thank Dr Birgitta Swolin and Dr Aziz Hussein for assistance with histopathology.

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  1. Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska University Hospital, Göteborg, Sweden

    A-K M Sjogren, K M E Andersson, O Khan, F J Olofsson, C Karlsson & M O Bergo

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  1. A-K M Sjogren
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Correspondence to M O Bergo.

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Sjogren, AK., Andersson, K., Khan, O. et al. Inactivating GGTase-I reduces disease phenotypes in a mouse model of K-RAS-induced myeloproliferative disease. Leukemia 25, 186–189 (2011). https://doi.org/10.1038/leu.2010.242

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