ArticleLeukemia2019
Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis.
Article in Leukemia, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 124 citations in OpenAlex.
- Lineage identity governs oncogene dependence in mouse NSCLC models of KRAS inhibitor resistance.Nature genetics · 2026Article
- Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration.bioRxiv : the preprint server for biology · 2026Article
- Oleuropein Regulates GSDME Methylation to Inhibit Tumor Growth and Enhance Radiosensitivity in Head and Neck Squamous Cell Carcinoma Via Inducing Pyroptosis.Applied biochemistry and biotechnology · 2026Article
- Exacerbation of inflammatory bone loss in TET2-driven clonal hematopoiesis.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.Nature cell biology · 2026Article
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- Inflammatory immune modulators of AML lung infiltration and respiratory failure.Nature immunology · 2026Article
- Pre-diagnostic clonal hematopoiesis of indeterminate potential among patients with a primary cancer and risk of second cancers.Leukemia · 2026Article
- Ligature-induced periodontitis promotesHaematologica · 2026Article
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- Inflammageing and clonal haematopoiesis interplay and their impact on human disease.Nature reviews. Molecular cell biology · 2026Review
- Functional equivalence of γ- and x-ray irradiation for long-term peripheral blood chimerism and acute myeloid leukemia transplant outcomes in mice.Experimental hematology · 2026Article
- Characterization of the clonal hierarchy and immunophenotype of PTPN11 mutations in acute myeloid leukemia.JCI insight · 2026Article
- Metallothionein 1 mediates growth and survival ofHaematologica · 2026Article
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- Inflammatory stromal and T cells mediate human bone marrow niche remodeling in clonal hematopoiesis and myelodysplasia.Nature communications · 2025Article
- GAB2 couples genetic drivers and signaling networks in acute myeloid leukemia.The Journal of clinical investigation · 2025Article
- Target practice: Opportunities for therapeutic intervention in CHIP and CCUS.Blood reviews · 2025Review
- Enforcement of stem-cell dormancy by nucleophosmin mutation is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis.Haematologica · 2025Article
- Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity.Cell stem cell · 2025Article
29 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Clonal hematopoiesis (CH) is a common aging-associated condition with increased risk of hematologic malignancy. Knowledge of the mechanisms driving evolution from CH to overt malignancy has been hampered by a lack of in vivo models that orthogonally activate mutant alleles. Here, we develop independently regulatable mutations in DNA methyltransferase 3A (Dnmt3a) and nucleophosmin 1 (Npm1), observed in human CH and AML, respectively. We find Dnmt3a mutation expands hematopoietic stem and multipotent progenitor cells (HSC/MPPs), modeling CH. Induction of mutant Npm1 after development of Dnmt3a-mutant CH causes progression to myeloproliferative disorder (MPD), and more aggressive MPD is observed with longer latency between mutations. MPDs uniformly progress to acute myeloid leukemia (AML) following transplant, accompanied by a decrease in HSC/MPPs and an increase in myeloid-restricted progenitors, the latter of which propagate AML in tertiary recipient mice. At a molecular level, progression of CH to MPD is accompanied by selection for mutations activating Ras/Raf/MAPK signaling. Progression to AML is characterized by additional oncogenic signaling mutations (Ptpn11, Pik3r1, Flt3) and/or mutations in epigenetic regulators (Hdac1, Idh1, Arid1a). Together, our study demonstrates that Npm1 mutation drives evolution of Dnmt3a-mutant CH to AML and rate of disease progression is accelerated with longer latency of CH.
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