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Cited by 206Myeloproliferative Neoplasms: Diagnosis and TreatmentAcute Myeloid Leukemia ResearchCancer Genomics and Diagnostics

Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in myeloproliferative neoplasms

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Van Egeren, Debra, Escabi, Javier, Nguyen, Maximilian, Liu, Shichen, Reilly, Christopher R., Patel, Sachin, Kamaz, Baransel, Kalyva, Maria +13 more·2021·Cell Stem Cell
DOI 10.1016/j.stem.2021.02.001PMC PMC7939520

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Abstract

ABSTRACT Some cancers originate from a single mutation event in a single cell. For example, blood cancers known as myeloproliferative neoplasms (MPN) are thought to originate through the acquisition of a driver mutation (most commonly JAK2 -V617F) in a hematopoietic stem cell (HSC). However, when the mutation first occurs in individual patients and how it impacts the behavior of HSCs in their native context is not known. Here we quantified the impact of the JAK2- V617F mutation on the proliferation dynamics of HSCs and the differentiation trajectories of their progenies in individual MPN patients. We reconstructed the lineage history of individual HSCs obtained from MPN patients using the patterns of spontaneous somatic mutations accrued in their genomes over time. Strikingly, we found that the JAK2- V617F mutation occurred in a single HSC several decades before MPN diagnosis — at age 9±2 years in a 34-year-old patient, and at age 19±3 years in a 63-year-old patient. For each patient, we inferred the number of mutated HSCs over time and computed their fitness. The population of JAK2 -mutated HSCs grew exponentially by 63±15% and 44±13% every year in the two patients, respectively. To contrast the differentiation trajectories of the JAK2 -mutated HSCs with those of healthy HSCs, we simultaneously measured the full transcriptome and somatic mutations in single hematopoietic stem and progenitor cells (HSPCs). We found that the fraction of JAK2 -mutant HSPCs varied significantly across different myeloid cell types within the same patient. The erythroid progenitor cells were often entirely JAK2 -mutant, even when the peripheral blood JAK2 -V617F allele burden was low. The novel biological insights uncovered by this work have implications for the prevention and treatment of MPN, as well as the accurate assessment of disease burden in patients. The technology platforms and computational frameworks developed here are broadly applicable to other types of hematological malignancies and cancers.

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  • Somatic DNMT3A variants can be acquired early in life.

    “Emerging evidence indicates somatic DNMT3A variants can be acquired early in life (12,13), before becoming almost ubiquitous in the aging population (14).”

    From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [12]

    The Abstract and Discussion report that JAK2-V617F was acquired early in life in two individuals, but they do not make that finding for DNMT3A. A search of our copy for DNMT3A and early-life acquisition found no passage addressing when somatic DNMT3A variants arise. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

  • These findings contrasted with the more subtle transcriptional impact of CALR-mutations, since mutated and wildtype cells are co-mingled throughout differentiation.

    “These findings contrasted with the more subtle transcriptional impact of CALR -mutations, since mutated and wildtype cells are co-mingled throughout differentiation 20,39 .”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [39]

    The Results section (‘JAK2-Mutant HSPCs Exhibit Fate Bias’; page unavailable) reports similar expression profiles and intermixing for JAK2-V617F and wild-type cells, not CALR-mutant cells. Searches for CALR and calreticulin found no passage in our copy addressing CALR mutations’ transcriptional impact or their distribution through differentiation. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Van Egeren, D., Escabi, J., Nguyen, M., Liu, S., Reilly, C. R., Patel, S., Kamaz, B., Kalyva, M., DeAngelo, D. J., Galinsky, I., Wadleigh, M., Winer, E. S., Luskin, M. R., Stone, R. M., Garcia, J. S., Hobbs, G. S., Camargo, F. D., Michor, F., Mullally, A., Cortes-Ciriano, I., & Hormoz, S.
Affiliations
  • Harvard University (US)
  • Dana-Farber Cancer Institute (US)
  • Boston Children's Hospital (US)
  • Brigham and Women's Hospital (US)
  • European Bioinformatics Institute (GB)
  • Massachusetts General Hospital (US)
  • Broad Institute (US)
Corresponding author
  • Mullally, Ann
  • Hormoz, Sahand
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2021-03
Volume
28
Issue
3
Pages
514-523.e9
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2021.02.001
PMC
PMC7939520
OpenAlex
W3132068389
Cited by
206
References
7
Citations by year
2026: 16 · 2025: 27 · 2024: 34 · 2023: 43 · 2022: 50 · 2021: 35 · 2020: 1
FWCI
22.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Bayer
  • Bayer Fund
  • Dana-Farber Cancer Institute
  • National Heart, Lung, and Blood Institute (R01HL158269)
  • Astellas Pharma US
  • Edward P. Evans Foundation (P01HL131477)
  • Ludwig Center at Harvard
  • European Molecular Biology Laboratory (R25GM109436)
  • Pfizer
  • National Institutes of Health (U54CA193461)
  • Novartis
  • Shire
  • AbbVie
  • Harvard Medical School
  • Merck
  • Takeda Pharmaceuticals U.S.A.
  • National Institute of General Medical Sciences (R00GM118910)
  • MPN Research Foundation (T32HL116324)
  • American Association for Cancer Research
  • Eli Lilly and Company
  • Harvard University
  • Gabrielle&apos;s Angel Foundation for Cancer Research (R01HL131835)
  • Barr Foundation
  • AstraZeneca
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
myeloproliferative neoplasms, JAK2 V617F mutation, hematopoietic stem cells, clonal evolution, lineage reconstruction, somatic mutations, stem cell self-renewal, stem cell differentiation, driver mutations, tumor origin, selective advantage
MeSH terms
Adolescent, Adult, Cell Differentiation, Child, Hematopoietic Stem Cells, Humans, Middle Aged, Mutation, Myeloproliferative Disorders, Neoplasms, Janus Kinase 2, Young Adult

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