Reconstructing the Lineage Histories and Differentiation Trajectories of Individual Cancer Cells in Myeloproliferative Neoplasms

Debra Van Egeren; Javier Escabi; Maximilian Nguyen; Shichen Liu; Christopher R Reilly; Sachin Patel; Baransel Kamaz; Maria Kalyva; Daniel J DeAngelo; Ilene Galinsky; Martha Wadleigh; Eric S Winer; Marlise R Luskin; Richard M Stone; Jacqueline S Garcia; Gabriela S Hobbs; Fernando D Camargo; Franziska Michor; Ann Mullally; Isidro Cortes-Ciriano; Sahand Hormoz

doi:10.1016/j.stem.2021.02.001

Reconstructing the Lineage Histories and Differentiation Trajectories of Individual Cancer Cells in Myeloproliferative Neoplasms

Cell Stem Cell. 2021 Mar 4;28(3):514-523.e9. doi: 10.1016/j.stem.2021.02.001. Epub 2021 Feb 22.

Authors

Debra Van Egeren¹, Javier Escabi², Maximilian Nguyen³, Shichen Liu⁴, Christopher R Reilly⁵, Sachin Patel⁶, Baransel Kamaz⁷, Maria Kalyva⁸, Daniel J DeAngelo⁵, Ilene Galinsky⁵, Martha Wadleigh⁵, Eric S Winer⁵, Marlise R Luskin⁵, Richard M Stone⁵, Jacqueline S Garcia⁵, Gabriela S Hobbs⁹, Fernando D Camargo¹⁰, Franziska Michor¹¹, Ann Mullally¹², Isidro Cortes-Ciriano¹³, Sahand Hormoz¹⁴

Affiliations

¹ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
² Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Research Scholar Initiative, Harvard Graduate School of Arts and Sciences, Cambridge, MA 02138, USA.
³ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
⁷ Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁸ European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
⁹ Leukemia Center, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
¹¹ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; The Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02115, USA; The Ludwig Center at Harvard, Boston, MA 02115, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: ann_mullally@dfci.harvard.edu.
¹³ European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK. Electronic address: icortes@ebi.ac.uk.
¹⁴ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: sahand_hormoz@hms.harvard.edu.

Abstract

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.

Keywords: JAK2; blood cancer; lineage tree; myeloproliferative neoplasm; single cell sequencing; stem cell dynamics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Cell Differentiation
Child
Hematopoietic Stem Cells
Humans
Janus Kinase 2 / genetics
Middle Aged
Mutation / genetics
Myeloproliferative Disorders* / genetics
Neoplasms*
Young Adult

Substances

Janus Kinase 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding