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.
authors.affiliation: Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Haeno
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
mesh_terms: D000818:Animals; D002453:Cell Cycle; D019070:Cell Lineage; D049109:Cell Proliferation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype
chemical_list: D053614:Janus Kinase 2