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PLoS Comput Biol. 2019 Jan 7;15(1):e1006664. doi: 10.1371/journal.pcbi.1006664. [Epub ahead of print]

Mutation, drift and selection in single-driver hematologic malignancy: Example of secondary myelodysplastic syndrome following treatment of inherited neutropenia.

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Systems Engineering Group, Silesian University of Technology, Gliwice, Poland.
Department of Pediatrics, Cleveland Clinic, Cleveland, OH, United States of America.
Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, United States of America.
Clinical Pediatrics, Division of Hospital Medicine, Stony Brook Children's Hospital, Stony Brook, New York.
Department of Statistics, Rice University, Houston, TX, United States of America.
Department of Preventive Medicine-Division of Biostatistics, Northwestern University, Chicago, IL United States of America.
Department of Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, IL United States of America.
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, United States of America.
Department of Bioengineering, Rice University, Houston, TX, United States of America.


Cancer development is driven by series of events involving mutations, which may become fixed in a tumor via genetic drift and selection. This process usually includes a limited number of driver (advantageous) mutations and a greater number of passenger (neutral or mildly deleterious) mutations. We focus on a real-world leukemia model evolving on the background of a germline mutation. Severe congenital neutropenia (SCN) evolves to secondary myelodysplastic syndrome (sMDS) and/or secondary acute myeloid leukemia (sAML) in 30-40%. The majority of SCN cases are due to a germline ELANE mutation. Acquired mutations in CSF3R occur in >70% sMDS/sAML associated with SCN. Hypotheses underlying our model are: an ELANE mutation causes SCN; CSF3R mutations occur spontaneously at a low rate; in fetal life, hematopoietic stem and progenitor cells expands quickly, resulting in a high probability of several tens to several hundreds of cells with CSF3R truncation mutations; therapeutic granulocyte colony-stimulating factor (G-CSF) administration early in life exerts a strong selective pressure, providing mutants with a growth advantage. Applying population genetics theory, we propose a novel two-phase model of disease development from SCN to sMDS. In Phase 1, hematopoietic tissues expand and produce tens to hundreds of stem cells with the CSF3R truncation mutation. Phase 2 occurs postnatally through adult stages with bone marrow production of granulocyte precursors and positive selection of mutants due to chronic G-CSF therapy to reverse the severe neutropenia. We predict the existence of the pool of cells with the mutated truncated receptor before G-CSF treatment begins. The model does not require increase in mutation rate under G-CSF treatment and agrees with age distribution of sMDS onset and clinical sequencing data.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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