Mutation, drift and selection in single-driver hematologic malignancy: Example of secondary myelodysplastic syndrome following treatment of inherited neutropenia
| Autor: | Hrishikesh M Mehta, Marta Iwanaszko, Marek Kimmel, Rosemary Braun, Seth J. Corey, Tomasz Wojdyla, Roberto Bertolusso, Taly Glaubach |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mutation rate Physiology Carcinogenesis Maternal Health medicine.disease_cause White Blood Cells 0302 clinical medicine Mutation Rate Animal Cells Receptors Colony-Stimulating Factor Medicine and Health Sciences Congenital Bone Marrow Failure Syndromes Secondary Acute Myeloid Leukemia Cell Cycle and Cell Division Biology (General) Mutation Ecology Stem Cells Cell Cycle Secondary Myelodysplastic Syndrome Obstetrics and Gynecology 3. Good health Leukemia Oncology Computational Theory and Mathematics Cell Processes Hematologic Neoplasms Modeling and Simulation Cellular Types Research Article Neutropenia QH301-705.5 Immune Cells Immunology Bone Marrow Cells Biology 03 medical and health sciences Cellular and Molecular Neuroscience Germline mutation Genetics medicine Humans Point Mutation Selection Genetic Congenital Neutropenia Molecular Biology Ecology Evolution Behavior and Systematics Blood Cells Models Genetic Point mutation Computational Biology Biology and Life Sciences Cell Biology Hematopoietic Stem Cells medicine.disease Hematopoiesis 030104 developmental biology Myelodysplastic Syndromes Birth Cancer research Women's Health Leukocyte Elastase Physiological Processes 030217 neurology & neurosurgery Granulocytes |
| Zdroj: | PLoS Computational Biology, Vol 15, Iss 1, p e1006664 (2019) PLoS Computational Biology |
| ISSN: | 1553-7358 |
| Popis: | 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. Author summary Cancer develops by multistep acquisition of mutations in a progenitor cell and its daughter cells. Severe congenital neutropenia (SCN) manifests itself through an inability to produce enough granulocytes to prevent infections. SCN commonly results from a germline ELANE mutation. Large doses of the blood growth factor granulocyte colony-stimulating factor (G-CSF) rescue granulocyte production. However, SCN frequently transforms to a myeloid malignancy, commonly associated with a somatic mutation in CSF3R, the gene encoding the G-CSF Receptor. We built a mathematical model of evolution for CSF3R mutation starting with bone marrow expansion at the fetal development stage and continuing with postnatal competition between normal and malignant bone marrow cells. We employ tools of probability theory such as multitype branching processes and Moran models modified to account for expansion of hematopoiesis during human development. With realistic coefficients, we obtain agreement with the age range at which malignancy arises in patients. In addition, our model predicts the existence of a pool of cells with mutated CSF3R before G-CSF treatment begins. Our findings may be clinically applied to intervene more effectively and selectively in SCN patients. |
| Databáze: | OpenAIRE |
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