ArticleNature cell biology2019
U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.
Article in Nature cell biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 157 papers.
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157 citing papers in PubMed, 249 citations in OpenAlex.
- Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents: a single-centre, single-arm, phase 2 trial.The Lancet. Haematology · 2020Trial
- Canakinumab or emavusertib for anemia in lower-risk MDS: results of the CANFIRE and LUCAS phase 2, open-label, multicenter trials.Communications medicine · 2026Article
- IP-LC-MS/MS-Based Identification of Candidate TPL2 (MAP3K8)-Associated Proteins in Porcine PK-15 Cells.Journal of mass spectrometry : JMS · 2026Article
- Nonsense-Mediated RNA Decay Is a Targetable Vulnerability in Splicing Factor Mutant Myeloid Neoplasms by Enhancing R-Loop Accumulation and DNA Damage.Cancer research · 2026Article
- Weakened macrophage antibacterial capacity in myelodysplastic syndrome.ImmunoHorizons · 2026Article
- Splicing-driven post-translational dysregulation: a new frontier for precision cancer medicine and immunotherapy.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Inflammatory Signatures in MDS: The Missing Link Between Genetics, Microenvironment, and Therapy.Cells · 2026Review
- Role of alternative splicing in cancer progression.Irish journal of medical science · 2026Review
- Application of next-generation sequencing in the treatment of myelodysplastic syndrome: from mechanisms to clinical practice.Blood science (Baltimore, Md.) · 2026Review
- Counting the CHIPs: The High-Stakes Role of Clonal Hematopoiesis in Multiple Myeloma.Biomedicines · 2026Review
- Article
- The actionable transcriptome: a framework for incorporating RNA sequencing into precision oncology.Nature reviews. Clinical oncology · 2026Review
- Targeting IL-1/IRAK1/4 signaling in acute myeloid leukemia stem cells following treatment and relapse.Leukemia · 2026Article
- Epigenetic alterations in Myeloid Malignancies.Advances in experimental medicine and biology · 2026Review
- Recent Advances in FLT3-Based Dual Inhibitors: A Promising Strategy for the Treatment of Acute Myeloid Leukemia.Current medicinal chemistry · 2026Review
- Unlocking the undruggable spliceosome: generative AI and structural dynamics in cancer therapy.Frontiers in cell and developmental biology · 2026Review
- IL-1 signaling and inflammasomes in acute myeloid leukemia: mechanisms and therapeutic opportunities.Cellular and molecular life sciences : CMLS · 2025Review
- Updates in low/intermediate-risk MDS.Hematology. American Society of Hematology. Education Program · 2025Review
- THRAP3 promotes ferroptosis resistance in acute myelocytic leukemia through SLU7-mediated alternative splicing of GIT2.Nature communications · 2025Article
- Molecular Insights and Therapeutic Advances in Low-Risk Myelodysplastic Neoplasms: A Clinical Review.Cancers · 2025Review
97 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 7 institutions in 2 countries.
Funding
Abstract
Spliceosome mutations are common in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but the oncogenic changes due to these mutations have not been identified. Here a global analysis of exon usage in AML samples revealed distinct molecular subsets containing alternative spliced isoforms of inflammatory and immune genes. Interleukin-1 receptor-associated kinase 4 (IRAK4) was the dominant alternatively spliced isoform in MDS and AML and is characterized by a longer isoform that retains exon 4, which encodes IRAK4-long (IRAK4-L), a protein that assembles with the myddosome, results in maximal activation of nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) and is essential for leukaemic cell function. Expression of IRAK4-L is mediated by mutant U2 small nuclear RNA auxiliary factor 1 (U2AF1) and is associated with oncogenic signalling in MDS and AML. Inhibition of IRAK4-L abrogates leukaemic growth, particularly in AML cells with higher expression of the IRAK4-L isoform. Collectively, mutations in U2AF1 induce expression of therapeutically targetable 'active' IRAK4 isoforms and provide a genetic link to activation of chronic innate immune signalling in MDS and AML.
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