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Frequent reconstitution of IDH2R140Q mutant clonal multilineage hematopoiesis following chemotherapy for acute myeloid leukemia

Leukemia volume 30, pages 1946–1950 (2016)Cite this article

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The full repertoire of recurrent genetic lesions associated with acute myeloid leukemia (AML) is now likely known, but the pathogenic contribution of each remains incompletely understood. Some are compatible with otherwise normal hematopoiesis. For example, aging humans with normal blood counts often exhibit hematopoietic sub-clones with mutations in DNMT3A, ASXL1 or TET2, among others, even though only a small minority ever develops myeloid malignancy.1, 2, 3 This suggests that such genetic lesions confer a competitive advantage to hematopoietic stem and progenitor cells to facilitate formation of a pre-leukemic stem cell pool receptive to secondary mutations for full-fledged leukemic transformation.4 Consistent with this, DNMT3A mutations often persist in blood many years after successful chemotherapy for AML.5 Conversely, other genetic lesions appear tightly associated with malignant transformation. For example, mutations in NPM1 are not seen with aging and their persistence following chemotherapy predicts for impending relapse.6

Mutations in IDH1 and IDH2 are found in 15–20% of patients with AML7 but are extremely rare drivers of clonal hematopoiesis in aging (~100-fold less frequent than mutations in DNMT3A, for example).1, 2, 3 It is currently unclear whether IDH mutant (IDHmut) clones persist in long-term clinical remission, and if so, what is their natural history, clinical fate, multilineage differentiation potential and relationship to other mutations. Establishing this is essential not only for biologic understanding, but also to establish therapeutic endpoints in patients treated with mutant IDH inhibitors.

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Acknowledgements

This work was supported by Cancer Research UK grant number C5759/A20971, a Bloodwise clinical training fellowship to DW and The Charlotte Carr Fighting Fund. We thank Jeff Barry, Abi Johnson, Chris Clark, Toni Grady and John Weightman for technical assistance, and John Chadwick for assistance with art work.

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Authors and Affiliations

  1. Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK

    D H Wiseman, E L Williams, T D D Somerville & T C P Somervaille

  2. Manchester Cancer Research Centre Biobank, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK

    D P Wilks

  3. Computational Biology, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK

    H Sun Leong

  4. Department of Haematology, The Christie NHS Foundation Trust, Manchester, UK

    M W Dennis

  5. Department of Clinical Chemistry, Metabolic Laboratory, Free University Medical Center, Amsterdam, The Netherlands

    E A Struys, A Bakkali & G S Salomons

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  1. D H Wiseman
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  2. E L Williams
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  7. E A Struys
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Correspondence to T C P Somervaille.

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Wiseman, D., Williams, E., Wilks, D. et al. Frequent reconstitution of IDH2R140Q mutant clonal multilineage hematopoiesis following chemotherapy for acute myeloid leukemia. Leukemia 30, 1946–1950 (2016). https://doi.org/10.1038/leu.2016.93

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