Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation
Abstract
Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). We identify mutational cooperation between Jak2V617F expression and Dnmt3a loss that drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated protein 9 (Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC, we show that Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen. Transcriptional analysis and integration with human data sets identified a core DNMT3A-driven gene-expression program shared across multiple models and contexts of Dnmt3a loss. Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a -/- Jak2V617F HSPC, driven by increased chromatin accessibility at enhancer elements. These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer-driven inflammatory signaling.
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Immune signaling pathways contribute to DNMT3A-associated hematologic conditions including aplastic anemia, myeloproliferative neoplasms, myelodysplastic syndrome, and acute myelogenous leukemia.
“Immune signaling pathways are known to contribute to DNMT3A-associated hematologic conditions including aplastic anemia, myeloproliferative neoplasms, myelodysplastic syndrome, and acute myelogenous leukemia (Azrakhsh et al., 2019; Jacquelin et al., 2018; Yoshizato et al., 2015).”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Jacquelin et al., 2018
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Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells
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Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling
Hormaechea-Agulla, D., Matatall, K. A., Le, D. T., Kain, B., Long, X., Kus, P., Jaksik, R., Challen, G. A., Kimmel, M., & King, K. Y. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.03.002 · Cited by 329 · see citing works
Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms
Fisher, D. A. C., Fowles, J. S., Zhou, A., & Oh, S. T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.683401 · Cited by 115 · see citing works
- Authors
- Jacquelin, S., Straube, J., Cooper, L., Vu, T., Song, A., Bywater, M., Baxter, E., Heidecker, M., Wackrow, B., Porter, A., Ling, V., Green, J., Austin, R., Kazakoff, S., Waddell, N., Hesson, L. B., Pimanda, J. E., Stegelmann, F., Bullinger, L., Döhner, K., Rampal, R. K., Heckl, D., Hill, G. R., & Lane, S. W.
- Affiliations
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
- QIMR Berghofer Medical Research Institute (AU)
- Garvan Institute of Medical Research (AU)
- UNSW Sydney (AU)
- Universität Ulm (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Memorial Sloan Kettering Cancer Center (US)
- Medizinische Hochschule Hannover (DE)
- The University of Queensland (AU)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2018-12-27
- Volume
- 132
- Issue
- 26
- Pages
- 2707-2721
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2898105308
- Cited by
- 99
- References
- 5
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 10 · 2023: 8 · 2022: 9 · 2021: 33 · 2020: 15 · 2019: 10 · 2018: 1
- FWCI
- 8.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- QIMR Berghofer Medical Research Institute
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- JAK2 V617F mutation, myelofibrosis, myeloproliferative neoplasms, polycythemia vera, hematopoietic stem and progenitor cells, enhancer activation, chromatin accessibility, inflammatory signaling, bone marrow fibrosis, self-renewal, transcriptional programs
- MeSH terms
- DNA Methyltransferase 3A, Animals, DNA (Cytosine-5-)-Methyltransferases, Hematopoietic Stem Cells, Humans, Mice, Mutant Strains, Signal Transduction, Hematologic Neoplasms, Amino Acid Substitution, Mutation, Missense, Mice, Janus Kinase 2, Primary Myelofibrosis
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