ArticleThe Journal of clinical investigation2024
Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 10 citations in OpenAlex.
- Article
- JAK-STAT signaling pathway in cancer: from molecular mechanisms to clinical intervention.Molecular cancer · 2026Review
- HTLV-1 subverts the innate immune effector gene IRF7 by viral HBZ protein for oncogenesis.Nature communications · 2026Article
- Asymmetry and redundancy of STAT5 paralogs across CD8Communications biology · 2026Article
- Real-time visualization of STAT activation in live cells using genetically encoded biosensors.Nature chemical biology · 2026Article
- Irisin-Treg crosstalk: unveiling a mechanism in neural cognitive regulation.Annals of medicine · 2025Review
- Targeting p16Leukemia · 2025Article
- Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia.Leukemia · 2025Article
- Recurrent Missense Driver STAT5BAnti-cancer agents in medicinal chemistry · 2025Article
- The structural influence of the oncogenic driver mutation N642H in the STAT5B SH2 domain.Protein science : a publication of the Protein Society · 2025Article
Corrections and comments
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Authors and funding
44 authors at 13 institutions in 8 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.
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