Title (eng)
Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia
Author
Nicole Prutsch
Mark W. Zimmerman
Diaaeldin I Abdallah
Alexander Pichler
Tea Pemovska
Carmen Schweicker
Emina Hubanic
Dennis Jungherz
Tony Andreas Müller
Kerstin Zimmel
Thomas Krausgruber
Christoph Bock
Roman Fleck
Elvin Dominic de Araujo
Patrick Thomas Gunning
Tero Aittokallio
Satu Mustjoki
Takaomi Sanda
Sylvia Hartmann
Gregor Hoermann
Torsten Haferlach
Philipp Bernhard Staber
Alfred Thomas Look
Marco Herling
Abstract (eng)
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.
Type (eng)
Language
[eng]
Persistent identifier
Is in series
Title (eng)
Journal of Clinical Investigation
Volume
134
Issue
8
ISSN
1558-8238
Issued
2024
Number of pages
17
Publication
American Society for Clinical Investigation
Version type (eng)
Date issued
2024
Access rights (eng)
License
Rights statement (eng)
© 2024, Suske et al.
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