Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia
Tobias Suske, et al.
Tobias Suske, et al.
View: Text | PDF
Research Article Genetics Hematology

Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia

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.

Authors

Tobias Suske, Helena Sorger, Gabriele Manhart, Frank Ruge, Nicole Prutsch, Mark W. Zimmerman, Thomas Eder, Diaaeldin I. Abdallah, Barbara Maurer, Christina Wagner, Susann Schönefeldt, Katrin Spirk, Alexander Pichler, Tea Pemovska, Carmen Schweicker, Daniel Pölöske, Emina Hubanic, Dennis Jungherz, Tony Andreas Müller, Myint Myat Khine Aung, Anna Orlova, Ha Thi Thanh Pham, Kerstin Zimmel, Thomas Krausgruber, Christoph Bock, Mathias Müller, Maik Dahlhoff, Auke Boersma, Thomas Rülicke, Roman Fleck, Elvin Dominic de Araujo, Patrick Thomas Gunning, Tero Aittokallio, Satu Mustjoki, Takaomi Sanda, Sylvia Hartmann, Florian Grebien, Gregor Hoermann, Torsten Haferlach, Philipp Bernhard Staber, Heidi Anne Neubauer, Alfred Thomas Look, Marco Herling, Richard Moriggl

×

Figure 5

Human T-ALL cell lines with high STAT5 activation display upregulated expression of TCR pathway genes.

Options: View larger image (or click on image) Download as PowerPoint
Human T-ALL cell lines with high STAT5 activation display upregulated ex...
(A) Basal levels of phosphorylated (pY) and total (t) STAT5, STAT3, and TCR pathway proteins in 9 T-ALL and 2 AML control cell lines, evaluated by Western blot analysis. Actin served as loading control. (B) Sanger sequencing of the SH2 and TAD domains of STAT5B. cDNA was obtained from isolated RNA of KOPT-K1 and DND-41 cells. The codon for amino acid position 642 is highlighted in blue. (C) Z scores of raw counts of TCR pathway genes from RNA-Seq data from 9 T-ALL cell lines. Three biological triplicates were acquired from each cell line and cell lines were arranged according to their pY-STAT5 level as determined by Western blot. (D) ChIP-Seq peak signals indicating STAT5B binding at the promoter region of 6 TCR pathway genes as indicated in 6 T-ALL cell lines. Normalized ChIP-Seq signal (CPM) is indicated on the y axis. (E) Peak analysis for STAT5B binding sites in TCR pathway genes from 6 T-ALL cell lines and indication of peak localization within respective genes or enhancers.