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
Main Authors:	Suske, Tobias, Sorger, Helena, Manhart, Gabriele, Ruge, Frank, Prutsch, Nicole, Zimmerman, Mark W, Eder, Thomas, Abdallah, Diaaeldin I, Maurer, Barbara, Wagner, Christina, Schönefeldt, Susann, Spirk, Katrin, Pichler, Alexander, Pemovska, Tea, Schweicker, Carmen, Pölöske, Daniel, Hubanic, Emina, Jungherz, Dennis, Müller, Tony Andreas, Aung, Myint Myat Khine, Orlova, Anna, Pham, Ha Thi Thanh, Zimmel, Kerstin, Krausgruber, Thomas, Bock, Christoph, Müller, Mathias, Dahlhoff, Maik, Boersma, Auke, Rülicke, Thomas, Fleck, Roman, de Araujo, Elvin Dominic, Gunning, Patrick Thomas, Aittokallio, Tero, Mustjoki, Satu, Sanda, Takaomi, Hartmann, Sylvia, Grebien, Florian, Hoermann, Gregor, Haferlach, Torsten, Staber, Philipp Bernhard, Neubauer, Heidi Anne, Look, Alfred Thomas, Herling, Marco, Moriggl, Richard
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 15-04-2024
Subjects:	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 Austria Denmark Germany Finland T cell development Genetics T cell receptor Hematology Leukemias
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI168536