ArticleThe Journal of clinical investigation2018
Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
77 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.
- Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells.Cell death & disease · 2018Pooled it
- Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Trial
- A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies.Seminars in hematology · 2021Trial
- Article
- FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.Research square · 2026Article
- FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.bioRxiv : the preprint server for biology · 2026Article
- DNA methyltransferase inhibitors in hematological malignancies and solid tumors.International journal of cancer · 2026Review
- Nucleophosmin 1 proteins as potential therapeutic targets in non-communicable chronic inflammatory diseases: a review of pathophysiological mechanisms.Frontiers in cell and developmental biology · 2026Review
- Combining drugs that bypass p53 to treat TP53-mutated leukemias.Blood advances · 2025Article
- Article
- Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia.Leukemia · 2025Article
- Abnormal nucleoli architecture and aggregate formation in nucleophosmin mutated acute myeloid leukaemia.Journal of cell science · 2025Article
- Review
- CD44 knockdown alters miRNA expression and their target genes in colon cancer.Frontiers in immunology · 2025Article
- Pharmacological restriction of genomic binding sites redirects PU.1 pioneer transcription factor activity.Nature genetics · 2024Article
- ARID3C Acts as a Regulator of Monocyte-to-Macrophage Differentiation Interacting with NPM1.Journal of proteome research · 2024Article
- Influence of genetic co-mutation on chemotherapeutic outcome in NPM1-mutated and FLT3-ITD wild-type AML patients.Cancer medicine · 2024Article
- Regulation of HOX gene expression in AML.Blood cancer journal · 2024Review
- Infrequent Presentations of ChronicCancers · 2024Review
- HOXA9 Regulome and Pharmacological Interventions in Leukemia.Advances in experimental medicine and biology · 2024Review
17 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
21 authors at 7 institutions in 4 countries.
Funding
Abstract
Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.1 (also known as SPI1). Mutant NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulomonocytic lineage fates, remained nuclear; but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating more than 500 granulocyte and monocyte terminal differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these noncytotoxic treatments extended survival by more than 160 days versus vehicle in a patient-derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant NPM1 represses monocyte and granulocyte terminal differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically directed dosing of clinical small molecules.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.