Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia
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 STAT...
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| Published in | The Journal of clinical investigation Vol. 134; no. 8; pp. 1 - 16 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
15.04.2024
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| Subjects | |
| Online Access | Get full text |
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| 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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| AbstractList | 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.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. 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 [STAT5B.sup.N642H] 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 [STAT5B.sup.N642H]. 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. 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 STAT5B N642H 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 STAT5B N642H . Hyperactive STAT5A or STAT5B initiates thymic T-cell development and transformation to T-cell acute lymphoblastic leukemia. 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 STAT5BNG42H 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 STATS dependent. We confirmed STATS binding to these genes using ChlP-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 STATSA and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STATS or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H. |
| Audience | Academic |
| Author | Boersma, Auke Spirk, Katrin Zimmel, Kerstin Bock, Christoph Aittokallio, Tero Hubanic, Emina Mustjoki, Satu Herling, Marco Hartmann, Sylvia Neubauer, Heidi Anne Zimmerman, Mark W. Wagner, Christina Look, Alfred Thomas Dahlhoff, Maik Schönefeldt, Susann Haferlach, Torsten Prutsch, Nicole Schweicker, Carmen Maurer, Barbara Jungherz, Dennis Pemovska, Tea Fleck, Roman Suske, Tobias Moriggl, Richard Staber, Philipp Bernhard Krausgruber, Thomas Eder, Thomas Müller, Tony Andreas Rülicke, Thomas Sanda, Takaomi de Araujo, Elvin Dominic Hoermann, Gregor Aung, Myint Myat Khine Ruge, Frank Pham, Ha Thi Thanh Orlova, Anna Manhart, Gabriele Pichler, Alexander Müller, Mathias Abdallah, Diaaeldin I. Pölöske, Daniel Gunning, Patrick Thomas Grebien, Florian Sorger, Helena |
| AuthorAffiliation | 23 Department of Hematology, Cellular Therapy and Hemostaseology, University of Leipzig, Leipzig, Germany 13 Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland 14 iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland 4 Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada 1 Institute of Animal Breeding and Genetics and 5 Department of Chemistry, University of Toronto, Toronto, Ontario, Canada 8 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria 2 Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA 7 Department I of Internal Medicine, Center for Integrated Oncology, Aachen-Bonn-Cologne-Duesseldorf, University of Cologne, Cologne, Germany 21 St. Anna Children’s |
| AuthorAffiliation_xml | – name: 2 Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria – name: 20 Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany – name: 15 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway – name: 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA – name: 1 Institute of Animal Breeding and Genetics and – name: 23 Department of Hematology, Cellular Therapy and Hemostaseology, University of Leipzig, Leipzig, Germany – name: 4 Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada – name: 10 Institute of in vivo and in vitro Models, University of Veterinary Medicine Vienna, Vienna, Austria – name: 6 Department of Medicine I, Clinical Division of Hematology, Medical University of Vienna, Vienna, Austria – name: 9 Institute of Artificial Intelligence, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria – name: 21 St. Anna Children’s Cancer Research Institute, Vienna, Austria – name: 19 Cancer Science Institute of Singapore and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore – name: 13 Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland – name: 14 iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland – name: 22 MLL Munich Leukemia Laboratory, Munich, Germany – name: 16 Oslo Centre for Biostatistics and Epidemiology, Faculty of Medicine, University of Oslo, Oslo, Norway – name: 24 Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Salzburg, Austria – name: 8 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – name: 11 Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria – name: 5 Department of Chemistry, University of Toronto, Toronto, Ontario, Canada – name: 17 Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland – name: 12 Janpix, London, United Kingdom – name: 7 Department I of Internal Medicine, Center for Integrated Oncology, Aachen-Bonn-Cologne-Duesseldorf, University of Cologne, Cologne, Germany – name: 18 Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38618957$$D View this record in MEDLINE/PubMed |
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| Keywords | T cell development Genetics T cell receptor Hematology Leukemias |
| Language | English |
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| Snippet | T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector... T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector... |
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| SubjectTerms | Acute lymphoblastic leukemia Acute lymphocytic leukemia Animals Antigen receptors, T cell Cancer therapies Cell activation Cell cycle Chemotherapy Cloning Comparative analysis Development and progression Disease Genes Genetic aspects Health aspects Humans Interleukin 7 receptors Kinases Leukemia Lymphocytes Lymphocytes T Lymphoma Medical prognosis Mice Mice, Transgenic Mutation Pediatrics Phenotypes Physiological aspects Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics Progenitor cells Protein-Tyrosine Kinases Receptors Receptors, Antigen, T-Cell - genetics Risk factors Signal Transduction Stat3 protein STAT5 Stat5 protein STAT5 Transcription Factor - genetics T cell receptors T cells Thymus gland Transcription factors Transgenic animals Transgenic mice Tyrosine ZAP-70 protein |
| Title | Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia |
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