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Chronic myelogenous leukemia

Frequent ASXL1 mutations in children and young adults with chronic myeloid leukemia

Leukemia volume 32, pages 2046–2049 (2018)Cite this article

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In the last decade a large number of somatic mutations affecting multiple pathways have been identified in myeloid malignancies with varying frequencies and combinations that overlap the different disease entities [1]. Initially, aberrations were discovered in genes that confer a growth advantage by altering signaling pathways and expression of key transcriptional targets. Over time, additional pathways such as epigenetic modification, RNA splicing, and the cohesin complex were found to be involved in myeloid leukemogenesis. Recent whole-exome screenings of large populations have revealed that many of these aberrations can also be found in healthy elderly people [2,3,4]. Clonal hematopoiesis with somatic mutations was observed in 10% of the population above 65 years of age, but in only 1% of people younger than 50 years of age [2]. The majority of the variants occurred in genes that have previously been implicated in myeloid cancers, most frequently DNMT3A, TET2, and ASXL1.

Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation t(9;22)(q34;q11), yielding the Philadelphia chromosome (Ph) and generating the BCR-ABL1 fusion gene that encodes a constitutively active protein tyrosine kinase [5]. The essential role of BCR-ABL1 for the pathogenesis of CML has been confirmed by the therapeutic success of selective BCR-ABL1 tyrosine kinase inhibitors (TKI), e.g., imatinib [6]. Recently, using a targeted deep next-generation sequencing (NGS) approach, we identified frequent mutations additionally to the BCR-ABL1 fusion gene in Ph-positive and Ph-negative clones of adult CML patients affecting the genes ASXL1, DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1, and ZRSR2 [7]. These mutations may be involved in the pathogenesis, clonal evolution, and progression of CML. However, since CML is predominantly a disease of the elderly population at least some of these aberrations might be age-related rather than leukemia-related molecular events.

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Acknowledgements

The excellent technical assistance of Mrs. Anja Waldau and Mrs. Susan Wittig is gratefully acknowledged. The study was supported by the Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R 15/20).

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Authors and Affiliations

  1. Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    Thomas Ernst, Melinda Busch, Jenny Rinke & Andreas Hochhaus

  2. Sektion für Hämatologie, Onkologie und Stammzelltransplantation, Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Jena, Jena, Germany

    Jana Ernst, James F. Beck & Bernd Gruhn

  3. MLL Münchner Leukämie Labor, München, Germany

    Claudia Haferlach

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Correspondence to Thomas Ernst.

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Ernst, T., Busch, M., Rinke, J. et al. Frequent ASXL1 mutations in children and young adults with chronic myeloid leukemia. Leukemia 32, 2046–2049 (2018). https://doi.org/10.1038/s41375-018-0157-2

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