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Myelodysplastic syndrome

Age-related mutations and chronic myelomonocytic leukemia

Abstract

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in 10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in 2 ARCH genes and 52% had 7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

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Acknowledgements

We thank Jonathan Schumacher (ARUP Laboratories) for assisting with the pyrosequencing confirmation, Anthony J Iovino for help with experiments, Jenny Ottley for administrative assistance and James Marvin (University of Utah) for help with fluorescence-activated cell sorting. We are grateful to Dr Nicholas Cross (Southampton, UK) and Dr Tim Ley (Washington University, Saint Louis) for helpful discussions. We also thank Agilent Technologies, Inc. for providing Sure Select XT2 targeted primers. This study was supported by grants from V Foundation for Cancer Research (JWT), The Leukemia & Lymphoma Society (MWD, JWT, BJD), Gabrielle’s Angel Foundation for Cancer Research (JWT), Charles and Ann Johnson Foundation (JG), the National Institutes of Health (5R00CA151457-04, 1R01CA183974-01, CA04963920, 1R01CA178397-01, P01CA049639 and P30 CA042014), the PPHC Human DNA Sequencing Grant, and the Utah Genome Project (MWD). The support and resources from the Center for High Performance Computing at the University of Utah are also gratefully acknowledged. JSK and AME are Fellows of the Leukemia & Lymphoma Society and SKT is a recipient of a fellowship award of the American Society of Hematology.

Author contributions

CCM and JSK conceived and designed the study, collected and assembled the data, analyzed and interpreted the data, and wrote the manuscript. SKT, MSZ, DY, ADP, KRR, AME, BKD collected and assembled the data. TWK, JWT, K-HD, BJD, JG provided study material. ZK, MY analyzed and interpreted the data. RLS collected and assembled the data, and analyzed and interpreted the data. TO collected and assembled the data, and wrote the manuscript. MWD conceived and designed the study, provided study material, analyzed and interpreted the data, and wrote the manuscript.

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Correspondence to M W Deininger.

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CCM and MWD report a potential related conflict of interest of research funding from Agilent Technologies, Inc. MWD also reports a potential related conflict of interest of research funding from Celgene, Inc. All other authors declare no conflict of interests.

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Mason, C., Khorashad, J., Tantravahi, S. et al. Age-related mutations and chronic myelomonocytic leukemia. Leukemia 30, 906–913 (2016). https://doi.org/10.1038/leu.2015.337

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