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Expression and mutation status of candidate kinases in multiple myeloma

Leukemia volume 21, pages 1124–1127 (2007)Cite this article

A Corrigendum to this article was published on 16 April 2008

Kinase hyperactivity often results in deregulation of cellular pathways involved in proliferation and survival. In multiple myeloma (MM), for example, the translocation of FGFR3, a receptor tyrosine kinase (RTK), to the immunoglobulin heavy chain locus is found in 15% of patients. FGFR3 mutations, activating the receptor, are found in both primary patient samples and cell lines, supporting the role of FGFR3 signaling in the pathogenesis of the disease. In recent years, several other kinases have also been reported to be somatically mutated in hematologic and solid organ malignancy. Furthermore, mutated kinases are ideal targets for therapeutics. These observations have led us (and others) to attempt kinome-wide sequencing in the hope of identifying other, as yet unidentified, somatic mutations in MM by focusing on RTKs. Of note, major sequencing efforts are currently being launched that may in part be duplicative. Subsequently, we report here our data to date derived from the sequencing of the kinase domains of 31 candidate genes and one kinase-regulatory gene CKS1B. Although we did not find recurrent mutation in genes other than FGFR3, we have noted non-synonymous sequence differences in ROR2, EGFR, GUCY2F and EPHB4 that are not present in dbSNP or pooled DNA from ethnically diverse populations that may now be further studied in larger cohorts of MM patients for any pharmacogenetic significance.

PCR amplification of genomic DNA was performed in 96-well plates using primers that have been previously described1, 2 or which were designed using the Primer3 program through the Canadian Bioinformatics Resource web portal (cbr-rbc.nrc-cnrc.gc.ca/index_e.php). Aliquots of PCR products were sequenced on 96-well plates without purification using nested sequencing primers. Sequence files generated from ABI 3730XL DNA analyzer were analyzed using SeqScape software (Applied Biosystems, Foster City, CA, USA) (ABI) and sequence changes were visually and manually inspected. Mutations were confirmed by reverse direction and repeat sequencing. In 17 of the genes sequenced, we covered 100% of the kinase domain whereas 15 of these kinases had their kinase regions partially sequenced between 55 and 85%. JAK2 was only sequenced within the mutation hot spot observed in lymphoproliferative disorders whereas CSK1B was fully sequenced.

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Acknowledgements

Financial support for this research was provided by seed funds from the Mclaughlin Center for Molecular Medicine, University of Toronto (AKS), research grant from the Multiple Myeloma Research Foundation (JOC, AKS), Canadian Institutes for Health Research (AKS), by the National Institutes of Health Grants CA55819 (JDS, FZ, BB) and CA97513 (JDS) and by the Fund to Cure Myeloma and Peninsula Community Foundation (JDS). We thank M Bali, V Nadeem, Z Li and E Wei for their technical assistance, and the patients who consented to the use of their anonymized samples for research.

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Authors and Affiliations

  1. Department of Medicine, University Health Network, McLaughlin Centre for Molecular Medicine and Ontario Cancer Institute, Toronto, Ontario, Canada

    J O Claudio, L Zhuang, Y X Zhu, S Trudel, E Masih-Khan & A K Stewart

  2. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    F Zhan & S W Scherer

  3. Department of Genetics, Hospital for Sick Children, The Centre for Applied Genomics, Toronto, Ontario, Canada

    R Khaja, K Sivananthan & J Shaughnessy

  4. Division of Hematology-Oncology, Department of Medicine, Mayo Clinic College of Medicine, Scottsdale, AZ, USA

    R Fonseca, P L Bergsagel & A K Stewart

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Correspondence to A K Stewart.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Claudio, J., Zhan, F., Zhuang, L. et al. Expression and mutation status of candidate kinases in multiple myeloma. Leukemia 21, 1124–1127 (2007). https://doi.org/10.1038/sj.leu.2404612

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