A progenitor cell origin of myeloid malignancies Journal Article
| Authors: | Haeno, H.; Levine, R. L.; Gilliland, D. G.; Michor, F. |
| Article Title: | A progenitor cell origin of myeloid malignancies |
| Abstract: | All cancers rely on cells that have properties of long-term self-renewal or "stemness" to maintain and propagate the tumor, but the cell of origin of most cancers is still unknown. Here, we design a stochastic mathematical model of hematopoietic stem and progenitor cells to study the evolutionary dynamics of cancer initiation. We consider different evolutionary pathways leading to cancer-initiating cells in JAK2V617F-positive myeloproliferative neoplasms (MPN): (i) the JAK2V617F mutation may arise in a stem cell; (ii) a progenitor cell may first acquire a mutation conferring self-renewal, followed by acquisition of the JAK2V617F mutation; (iii) the JAK2V617F mutation may first emerge in a progenitor cell, followed by a mutation conferring self-renewal; and (iv) a mutation conferring self-renewal to progenitors may arise in the stem cell population without causing a change in the stem cell's phenotype, followed by the JAK2V617F mutation emerging in a progenitor cell. We find mathematical evidence that a progenitor is the most likely cell of origin of JAK2V617F-mutant MPN. These results may also have relevance to other tumor types arising in tissues that are organized as a differentiation hierarchy. |
| Keywords: | myeloproliferative disorders; unclassified drug; gene mutation; mutation; myeloproliferative disorder; janus kinase 2; cell proliferation; phenotype; animals; cell cycle; cell differentiation; cell lineage; stem cell; neoplastic stem cells; hematopoietic system; models, genetic; cancer modeling; cell of origin; evolutionary dynamics; protein jak2v617f; myeloid progenitor cells |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 106 |
| Issue: | 39 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2009-09-29 |
| Start Page: | 16616 |
| End Page: | 16621 |
| Language: | English |
| DOI: | 10.1073/pnas.0908107106 |
| PUBMED: | 19805346 |
| PROVIDER: | scopus |
| PMCID: | PMC2757818 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 30 November 2010" - "CODEN: PNASA" - "Source: Scopus" |
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