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High-throughput mutational screen of the tyrosine kinome in chronic myelomonocytic leukemia

Leukemia volume 23, pages 406–409 (2009)Cite this article

Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia are characterized by persistent monocytosis and combined dysplastic morphology with features of a myeloproliferative syndrome.1 Together with atypical chronic myelogenous leukemia (aCML) and the category of unclassifiable myelodysplastic/myeloproliferative diseases, they belong to the same WHO diagnostic group.1 Activation of the RAS signaling pathway is almost universal in juvenile myelomonocytic leukemia, albeit the result of diverse genetic lesions, including mutations of N-RAS, K-RAS, NF-1 and PTPN11 (reviewed in Lauchle et al.2). The genetics of CMML and aCML is yet more complex. Various studies reported activating mutations of N-RAS and K-RAS in 20 to almost 60% of patients, and mutations in PTPN11 in isolated cases.3, 4 NF-1 (neurofibromatosis 1) has not been studied extensively, but one study of patients with MDS (including CMML) and acute myeloid leukemia did not find major rearrangements at the genomic level.5 In contrast to juvenile myelomonocytic leukemia, activating mutations in tyrosine kinases, including PDGFRA/B, KIT, FGFR1, FLT3, CSF-1R and JAK2, have also been implicated in small subsets of patients.6, 7, 8, 9, 10, 11 Mutations in RAS or in tyrosine kinases primarily drive proliferation, and are collectively referred to as ‘type 1’ mutations. Type 1 mutations do not usually coexist within the same leukemic clone, although there are occasional exceptions.8, 12 The cumulative frequency of previously reported mutations in RAS or a tyrosine kinase in CMML and aCML is not known, as no comprehensive mutational analysis has been performed in such patients. However, given that most of the reported tyrosine kinase mutations are infrequent, it is likely that screening for established mutations in specific kinases and RAS would leave a considerable proportion of cases unexplained. We therefore hypothesized that previously unidentified tyrosine kinase mutations may be involved in the pathogenesis of CMML and aCML. To test this, we performed a comprehensive mutational screen of the tyrosine kinome in a cohort of such patients.

Thirty-two patients were included in this study. In 26 the disease was classified as CMML, in 5 as aCML and in 1 as an unclassifiable myelodysplastic/myeloproliferative disorder (Table 1). Karyotyping was unavailable for eight CMML patients, reflecting the fact that some samples were acquired up to 20 years ago. In five patients without available karyotype, BCR-ABL was excluded by fluorescence in situ hybridization (FISH). There was no evidence for a rearrangement of chromosome 5 in any of the patients with available cytogenetics. Primers were designed to amplify the activation loops and/or juxtamembrane domains of all 90 known human tyrosine kinases, the JH2 domains of JAK1, JAK2, JAK3 and TYK2, as well as the entire coding sequence of H-RAS, K-RAS and N-RAS. To exclude single nucleotide polymorphisms, all candidate mutations were compared with public databases and, where appropriate, with a panel of 96 samples of normal genomic DNA from individuals of similar ethnic background (for a list of primers and conditions, see Loriaux et al.13).

Table 1 Patient characteristics and mutations
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Acknowledgements

This study was supported in part by NHLBI Grant HL082978-01 (MWD), and the Leukemia and Lymphoma Society (MWD).

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Author notes

  1. J W Tyner and M M Loriaux: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, OR, USA

    J W Tyner, H Erickson, C A Eide, J Deininger, M MacPartlin, S G Willis, B J Druker, T Kovacsovics, R Maziarz & M W Deininger

  2. Department of Pathology, Oregon Health and Science University, Portland, OR, USA

    M M Loriaux

  3. Department of Hematology/Oncology, University of Leipzig, Leipzig, Germany

    T Lange

  4. Howard Hughes Medical Institute, Portland, OR, USA

    B J Druker

  5. Klinik für Hämatologie, Onkologie und klinische Immunologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, GermanyE-mail: deininge@ohsu.edu,

    N Gattermann

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

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Tyner, J., Loriaux, M., Erickson, H. et al. High-throughput mutational screen of the tyrosine kinome in chronic myelomonocytic leukemia. Leukemia 23, 406–409 (2009). https://doi.org/10.1038/leu.2008.187

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