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

Simple item page
dc.citation.articleNumbere1006664en_US
dc.citation.issueNumber1en_US
dc.citation.journalTitlePLoS Computational Biologyen_US
dc.citation.volumeNumber15en_US
dc.contributor.authorWojdyla, Tomaszen_US
dc.contributor.authorMehta, Hrishikeshen_US
dc.contributor.authorGlaubach, Talyen_US
dc.contributor.authorBertolusso, Robertoen_US
dc.contributor.authorIwanaszko, Martaen_US
dc.contributor.authorBraun, Rosemaryen_US
dc.contributor.authorCorey, Seth J.en_US
dc.contributor.authorKimmel, Mareken_US
dc.date.accessioned2019-12-11T15:44:18Zen_US
dc.date.available2019-12-11T15:44:18Zen_US
dc.date.issued2019en_US
dc.description.abstractCancer 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.en_US
dc.identifier.citationWojdyla, Tomasz, Mehta, Hrishikesh, Glaubach, Taly, et al.. "Mutation, drift and selection in single-driver hematologic malignancy: Example of secondary myelodysplastic syndrome following treatment of inherited neutropenia." <i>PLoS Computational Biology,</i> 15, no. 1 (2019) Public Library of Science: https://doi.org/10.1371/journal.pcbi.1006664.en_US
dc.identifier.digitaljournal.pcbi.1006664en_US
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1006664en_US
dc.identifier.urihttps://hdl.handle.net/1911/107846en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleMutation, drift and selection in single-driver hematologic malignancy: Example of secondary myelodysplastic syndrome following treatment of inherited neutropeniaen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
journal.pcbi.1006664.pdf
Size:
1.65 MB
Format:
Adobe Portable Document Format
Download
Collections
Faculty Publications
Bioengineering Publications
Statistics Publications