Self-Renewal of Single Mouse Hematopoietic Stem Cells Is Reduced by JAK2V617F Without Compromising Progenitor Cell Expansion
| Autor: | Hinal Tanna, Dean C. Pask, Benjamin D. Simons, Juergen Fink, Kristina Kirschner, Yvonne Silber, Rachel Sneade, Tina L. Hamilton, David G. Kent, Anthony R. Green, Juan Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Mouse
Cellular differentiation Cell Count medicine.disease_cause Hematologic Cancers and Related Disorders Mice 0302 clinical medicine Molecular Cell Biology Bone Marrow and Stem Cell Transplantation Gene Knock-In Techniques Biology (General) Cellular Stress Responses 0303 health sciences General Neuroscience Stem Cells Cell Cycle Hematopoietic Stem Cell Transplantation Hematopoietic stem cell food and beverages Cell Differentiation Animal Models Hematology 3. Good health Cell biology Endothelial stem cell Haematopoiesis Adult Stem Cells medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Medicine Stem cell Cellular Types General Agricultural and Biological Sciences Cell Division Research Article Hematopoietic Progenitor Cells QH301-705.5 Biology General Biochemistry Genetics and Molecular Biology Cell Growth 03 medical and health sciences Model Organisms Antigens CD Leukemias medicine Animals Humans Cell Lineage Progenitor cell 030304 developmental biology Cell Proliferation Myeloproliferative Disorders General Immunology and Microbiology Correction Cancers and Neoplasms Janus Kinase 2 Hematopoietic Stem Cells Clone Cells Hematopoiesis Transplantation Amino Acid Substitution Immunology Mutation Carcinogenesis Cytometry |
| Zdroj: | PLoS Biology PLoS Biology, Vol 11, Iss 6, p e1001576 (2013) |
| ISSN: | 1545-7885 1544-9173 |
| Popis: | In this study, single cell assays and mathematical modeling demonstrate that a single oncogenic point mutation can negatively affect hematopoietic stem cells while leaving progenitor cell expansion intact. Recent descriptions of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumors. Human myeloproliferative neoplasms (MPNs) are thought to reflect transformation of a hematopoietic stem cell (HSC) and the majority harbor an acquired V617F mutation in the JAK2 tyrosine kinase, making them a paradigm for studying the early stages of tumor establishment and progression. The consequences of activating tyrosine kinase mutations for stem and progenitor cell behavior are unclear. In this article, we identify a distinct cellular mechanism operative in stem cells. By using conditional knock-in mice, we show that the HSC defect resulting from expression of heterozygous human JAK2V617F is both quantitative (reduced HSC numbers) and qualitative (lineage biases and reduced self-renewal per HSC). The defect is intrinsic to individual HSCs and their progeny are skewed toward proliferation and differentiation as evidenced by single cell and transplantation assays. Aged JAK2V617F show a more pronounced defect as assessed by transplantation, but mice that transform reacquire competitive self-renewal ability. Quantitative analysis of HSC-derived clones was used to model the fate choices of normal and JAK2-mutant HSCs and indicates that JAK2V617F reduces self-renewal of individual HSCs but leaves progenitor expansion intact. This conclusion is supported by paired daughter cell analyses, which indicate that JAK2-mutant HSCs more often give rise to two differentiated daughter cells. Together these data suggest that acquisition of JAK2V617F alone is insufficient for clonal expansion and disease progression and causes eventual HSC exhaustion. Moreover, our results show that clonal expansion of progenitor cells provides a window in which collaborating mutations can accumulate to drive disease progression. Characterizing the mechanism(s) of JAK2V617F subclinical clonal expansions and the transition to overt MPNs will illuminate the earliest stages of tumor establishment and subclone competition, fundamentally shifting the way we treat and manage cancers. Author Summary Recent descriptions of the existence of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumours. In this study, we focus on understanding the stem cell defect that results from a mutation in the JAK2 tyrosine kinase gene, which is present in the majority of patients with myeloproliferative neoplasms (MPNs), a group of clonal bone marrow diseases that are characterised by the overproduction of mature blood cells and increased frequency of leukaemia development. By using single-cell assays and mathematical modeling, followed by the individual assessment of daughter cells from single HSCs, we identify a distinct cellular mechanism that differentially affects stem cell and progenitor cell expansion. Specifically, we show that this single point mutation can negatively affect HSCs while leaving progenitor cell expansion intact. Characterising the mechanisms that link JAK2 mutations with clonal expansions that eventually lead to development of MPNs will inform our understanding of the earliest stages of tumour establishment and of the competition between subclones of proliferating progenitor/stem cells. These findings have direct relevance to all cancers of a suspected stem cell origin. |
| Databáze: | OpenAIRE |
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