Tobias Suske Tobias Suske Helena Sorger Helena Sorger Gabriele Manhart Gabriele Manhart Frank Ruge Frank Ruge Nicole Prutsch Nicole Prutsch Mark W. Zimmerman Mark W. Zimmerman Thomas Eder Thomas Eder Diaaeldin I Abdallah Diaaeldin I Abdallah Barbara Maurer Barbara Maurer Christina Wagner Christina Wagner Susann Schönefeldt Susann Schönefeldt Katrin Spirk Katrin Spirk Alexander Pichler Alexander Pichler Tea Pemovska Tea Pemovska Carmen Schweicker Carmen Schweicker Daniel Pölöske Daniel Pölöske Emina Hubanic Emina Hubanic Dennis Jungherz Dennis Jungherz Tony Andreas Müller Tony Andreas Müller Myint Myat Khine Aung Myint Myat Khine Aung Anna Orlova Anna Orlova Ha Thi Thanh Pham Ha Thi Thanh Pham Kerstin Zimmel Kerstin Zimmel Thomas Krausgruber Thomas Krausgruber Christoph Bock Christoph Bock Mathias Müller Mathias Müller Maik Dahlhoff Maik Dahlhoff Auke Boersma Auke Boersma Thomas Rülicke Thomas Rülicke Roman Fleck Roman Fleck Elvin Dominic de Araujo Elvin Dominic de Araujo Patrick Thomas Gunning Patrick Thomas Gunning Tero Aittokallio Tero Aittokallio Satu Mustjoki Satu Mustjoki Takaomi Sanda Takaomi Sanda Sylvia Hartmann Sylvia Hartmann Florian Grebien Florian Grebien Gregor Hoermann Gregor Hoermann Torsten Haferlach Torsten Haferlach Philipp Bernhard Staber Philipp Bernhard Staber Heidi Anne Neubauer-Sedy Heidi Anne Neubauer-Sedy Alfred Thomas Look Alfred Thomas Look Marco Herling Marco Herling Richard Moriggl Richard Moriggl American Society for Clinical Investigation 2024 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. PDFDocument eng 2025-07-30T12:06:30.143960Z 2024 10122395 b application/pdf http://creativecommons.org/licenses/by/4.0/