Journal
CELL STEM CELL
Volume 28, Issue 3, Pages 514-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2021.02.001
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Funding
- NIH NIGMS [R00GM118910, R25GM109436]
- DFCI BCB Fund Award
- Jayne Koskinas Ted Giovanis Foundation
- William F. Milton Fund at Harvard University
- AACR-MPM Oncology Charitable Foundation Transformative Cancer Research grant
- Gabrielle's Angel Foundation for Cancer Research
- Claudia Adams Barr Program in Cancer Research
- MPN Research Foundation
- Leukemia & Lymphoma Society
- NSF-Simons Center for Mathematical and Statistical Analysis of Biology at Harvard [1764269]
- Harvard Quantitative Biology Initiative
- Ludwig Center at Harvard
- Dana-Farber Cancer Institute Physical Science-Oncology Center [NIH U54CA193461]
- EMBL
- Edward Evans MDS Foundation
- NIH NHLBI [R01HL158269, R01HL131835, T32HL116324, P01HL131477]
- Research Computing Group, at Harvard Medical School
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The JAK2-V617F mutation affects the self-renewal and differentiation dynamics of HSCs in MPNs patients, helping to reconstruct cancer lineages, with the mutation likely occurring several decades before diagnosis and providing a selective advantage for mutant HSCs.
Some cancers originate from a single mutation event in a single cell. Blood cancers known as myeloproliferative neoplasms (MPNs) are thought to originate when a driver mutation is acquired by a hematopoietic stem cell (HSC). However, when the mutation first occurs in individuals and how it affects the behavior of HSCs in their native context is not known. Here we quantified the effect of the JAK2-V617F mutation on the self-renewal and differentiation dynamics of HSCs in treatment-naive individuals with MPNs and reconstructed lineage histories of individual HSCs using somatic mutation patterns. We found that JAK2-V617F mutations occurred in a single HSC several decades before MPN diagnosis-at age 9 +/- 2 years in a 34-year-old individual and at age 19 +/- 3 years in a 63-year-old individual-and found that mutant HSCs have a selective advantage in both individuals. These results highlight the potential of harnessing somatic mutations to reconstruct cancer lineages.
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