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| Status |
Public on Apr 15, 2024 |
| Title |
Hyperactive STAT5 Hijacks T-Cell Receptor Signaling and Drives Immature T-Cell Acute Lymphoblastic Leukemia |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T-cell cancer.
Mutations in IL7RA were analyzed genetically, but downstream effector functions such as
STAT5A/B 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 to STAT5A hyperactive variants in transgenic mice. Enhanced STAT5
activity caused disrupted T-cell development and promoted an early T-cell progenitor (ETP)-
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 first 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 chemo-resistant clones
carrying STAT5BN642H.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data from murine thymocytes in wildtype, Rag deficient, Stat5a and Stat5b gain of function mutations in 3 sates of T-cell differentiation (determined by CD4 and CD8 cell surface markers)
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| Web link |
http://DOI: 10.1172/JCI168536
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| Contributor(s) |
Suske T, Sorger H, Ruge F, Prutsch N, Zimmerman MW, Eder T, Maurer B, Wagner C, Schönefeldt S, Spirk K, Pölöske D, Jungherz D, Müller TA, Aung MM, Pham HT, Zimmel K, Krausgruber T, Bock C, Müller M, Dahlhoff M, Boersma A, Rülicke T, Fleck R, Gunning PT, Aittokallio T, Sanda SM, Hartmann S, Grebien F, Hoermann G, Haferlach T, Staber PB, Neubauer HA, Look AT, Herling M, Moriggl R, Manhart G, Abdallah D, Hubanic E, de Araujo ED |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Nov 28, 2022 |
| Last update date |
Apr 15, 2024 |
| Contact name |
Tobias Suske |
| E-mail(s) |
tobias.suske@vetmeduni.ac.at
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| Organization name |
University of Veterinary Medicine
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| Department |
Functional Cancer Genomics
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| Lab |
Moriggl
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| Street address |
Veterinärplatz 1
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| City |
Vienna |
| State/province |
Vienna |
| ZIP/Postal code |
1210 |
| Country |
Austria |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (51)
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| GSM6757820 |
CD4, CD8 double negative thymocytes in Rag2 deficient background. Mouse 3 [R2a_DN_3] |
| GSM6757821 |
CD4, CD8 double negative thymocytes in Rag2 deficient background. Mouse 4 [R2a_DN_4] |
| GSM6757822 |
CD4, CD8 double negative thymocytes in Rag2 deficient background. Mouse 5 [R2a_DN_5] |
| GSM6757823 |
CD4, CD8 double negative thymocytes in Stat5AS710F background. Mouse 1 [S5a_DN_1] |
| GSM6757824 |
CD4, CD8 double negative thymocytes in Stat5AS710F background. Mouse 3 [S5a_DN_3] |
| GSM6757825 |
CD4, CD8 double negative thymocytes in Stat5AS710F background. Mouse 6 [S5a_DN_6] |
| GSM6757826 |
CD8 positive thymocytes in wildtype background. Mouse 1 [WT_CD8_1] |
| GSM6757827 |
CD8 positive thymocytes in wildtype background. Mouse 2 [WT_CD8_2] |
| GSM6757828 |
CD8 positive thymocytes in wildtype background. Mouse 5 [WT_CD8_5] |
| GSM6757829 |
CD4, CD8 double negative thymocytes in wildtype background. Mouse 1 [WT_DN_1] |
| GSM6757830 |
CD4, CD8 double negative thymocytes in wildtype background. Mouse 2 [WT_DN_2] |
| GSM6757831 |
CD4, CD8 double negative thymocytes in wildtype background. Mouse 5 [WT_DN_5] |
| GSM6757832 |
CD4, CD8 double positive thymocytes in wildtype background. Mouse 1 [WT_DP_1] |
| GSM6757833 |
CD4, CD8 double positive thymocytes in wildtype background. Mouse 2 [WT_DP_2] |
| GSM6757834 |
CD4, CD8 double positive thymocytes in wildtype background. Mouse 5 [WT_DP_5] |
| GSM6757835 |
CD8 positive thymocytes in Rag deficient and Stat5aS710F background. Mouse 1 [R2S5a_CD8_1] |
| GSM6757836 |
CD8 positive thymocytes in Rag deficient and Stat5aS710F background. Mouse 2 [R2S5a_CD8_2] |
| GSM6757837 |
CD8 positive thymocytes in Rag deficient and Stat5aS710F background. Mouse 6 [R2S5a_CD8_6] |
| GSM6757838 |
CD4, CD8 double negative in Rag deficient and Stat5aS710F background. Mouse 3 [R2S5a_DN_3] |
| GSM6757839 |
CD4, CD8 double negative in Rag deficient and Stat5aS710F background. Mouse 4 [R2S5a_DN_4] |
| GSM6757840 |
CD4, CD8 double negative in Rag deficient and Stat5aS710F background. Mouse 6 [R2S5a_DN_6] |
| GSM6757841 |
CD4, CD8 double positive in Rag deficient and Stat5aS710F background. Mouse 3 [R2S5a_DP_3] |
| GSM6757842 |
CD4, CD8 double positive in Rag deficient and Stat5aS710F background. Mouse 4 [R2S5a_DP_4] |
| GSM6757843 |
CD4, CD8 double positive in Rag deficient and Stat5aS710F background. Mouse 6 [R2S5a_DP_6] |
| GSM6757844 |
CD4 negative, CD8 positive thymocytes in Stat5AS710F background. Mouse 1 [S5a_CD8_1] |
| GSM6757845 |
CD4 negative, CD8 positive thymocytes in Stat5AS710F background. Mouse 3 [S5a_CD8_3] |
| GSM6757846 |
CD4 negative, CD8 positive thymocytes in Stat5AS710F background. Mouse 6 [S5a_CD8_6] |
| GSM6757847 |
CD4 positive, CD8 positive thymocytes in Stat5AS710F background. Mouse 1 [S5a_DP_1] |
| GSM6757848 |
CD4 positive, CD8 positive thymocytes in Stat5AS710F background. Mouse 3 [S5a_DP_3] |
| GSM6757849 |
CD4 positive, CD8 positive thymocytes in Stat5AS710F background. Mouse 6 [S5a_DP_6] |
| GSM6757850 |
CD4 negative, CD8 positive thymocytes in Stat5AS710F background. Mouse 104 [R2S5b_CD8_104] |
| GSM6757851 |
CD4 negative, CD8 positive thymocytes in Stat5AS710F and Rag2 deficient backbackground. Mouse 104 [R2S5b_DN_104] |
| GSM6757852 |
CD4 negative, CD8 positive thymocytes in Stat5AS710F background. Mouse 104 [R2S5b_DP_104] |
| GSM6757853 |
CD4, CD8 double negative thymocytes in Rag2 deficient background. Mouse 106 [R2b_DN_106] |
| GSM6757854 |
CD4 negative, CD8 positive thymocytes in Rag2 and STAT5BN642H double deficient background. Mouse 129 [R2S5b_CD8_129] |
| GSM6757855 |
CD4, CD8 double positive thymocytes in Rag2 and STAT5BN642H double deficient background. Mouse 129 [R2S5b_DP_129] |
| GSM6757856 |
CD4 negative, CD8 positive thymocytes in STAT5BN642H deficient background. Mouse 131 [S5b_CD8_131] |
| GSM6757857 |
CD4, CD8 double negative thymocytes in STAT5BN642H deficient background. Mouse 131 [S5b_DN_131] |
| GSM6757858 |
CD4, CD8 double positive thymocytes in STAT5BN642H deficient background. Mouse 131 [S5b_DP_131] |
| GSM6757859 |
CD4 negative, CD8 positive thymocytes in STAT5BN642H deficient background. Mouse 132 [S5b_CD8_132] |
| GSM6757860 |
CD4, CD8 double negative thymocytes in STAT5BN642H deficient background. Mouse 132 [S5b_DN_132] |
| GSM6757861 |
CD4, CD8 double positive thymocytes in STAT5BN642H deficient background. Mouse 132 [S5b_DP_132] |
| GSM6757862 |
CD4, CD8 double negative thymocytes in STAT5BN642H deficient background. Mouse 65 [S5b_DN_65] |
| GSM6757863 |
CD4 negative, CD8 positive thymocytes in STAT5BN642H deficient background. Mouse 67 [S5b_CD8_67] |
| GSM6757864 |
CD4, CD8 double positive thymocytes in STAT5BN642H deficient background. Mouse 67 [S5b_DP_67] |
| GSM6757865 |
CD4, CD8 double negative thymocytes in Rag2 deficient background. Mouse 90 [R2b_DN_90] |
| GSM6757866 |
CD4, CD8 double negative thymocytes in Rag2 and STAT5BN642H double deficient background. Mouse 93 [R2S5b_DN_93] |
| GSM6757867 |
CD4 negative, CD8 positive thymocytes in Rag2 and STAT5BN642H double deficient background. Mouse 94 [R2S5b_CD8_94] |
| GSM6757868 |
CD4, CD8 double negative thymocytes in Rag2 and STAT5BN642H double deficient background. Mouse 94 [R2S5b_DN_94] |
| GSM6757869 |
CD4, CD8 double positive thymocytes in Rag2 and STAT5BN642H double deficient background. Mouse 94 [R2S5b_DP_94] |
| GSM6757870 |
CD4, CD8 double negative thymocytes in Rag2 deficient background. Mouse 95 [R2b_DN_95] |
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| Relations |
| BioProject |
PRJNA906030 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE218858_RAW.tar |
9.5 Mb |
(http)(custom) |
TAR (of TSV) |
| GSE218858_all_DIFF_N642H_DE_result_tables.xlsx |
10.3 Mb |
(ftp)(http) |
XLSX |
| GSE218858_all_DIFF_S710F_DE_result_tables.xlsx |
10.3 Mb |
(ftp)(http) |
XLSX |
| GSE218858_all_GT_N642H_DE_result_tables.xlsx |
11.8 Mb |
(ftp)(http) |
XLSX |
| GSE218858_all_GT_S710F_DE_result_tables.xlsx |
11.4 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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