Hyperactive STAT5 Hijacks T-Cell Receptor Signaling and Drives Immature T-Cell Acute Lymphoblastic Leukemia
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ABSTRACT:
PROVIDER: PRJNA906030 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22426923.fastq.gz | Fastqsanger.gz | |||
| SRR22426924.fastq.gz | Fastqsanger.gz | |||
| SRR22426925.fastq.gz | Fastqsanger.gz | |||
| SRR22426926.fastq.gz | Fastqsanger.gz | |||
| SRR22426927.fastq.gz | Fastqsanger.gz |
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Project description: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.
2024-04-15 | GSE218858 | GEO
Project description: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.
| S-EPMC11014662 | biostudies-literature
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T-cell cancer. Hotspot mutations in JAK-STAT pathway members IL7R, JAK1 and JAK3 were analyzed in depth, but the role of STAT5A or STAT5B in T-cell development or T-ALL transformation is unclear. Importantly, the driver mutation STAT5BN642H encodes the most frequent activating STAT5 variant in T-ALL and it correlated with disease relapse upon chemotherapy. Here, we show that STAT5BN642H promotes T-ALL-like cancer in mice and transcriptionally upregulates a collection of genes that are involved in T-cell receptor signaling (TCR), even in the absence of surface TCR. Importantly, these genes were also overexpressed in human T-ALL patients. Moreover, T-ALL cells were sensitive to pharmacologic inhibition of STAT3/5 or ZAP70 activity. Collectively, we discovered how hyperactive STAT5 induces and accelerates T-ALL and we suggest therapeutic targeting using selective ZAP70 or STAT5 activity inhibitors in a subgroup of T-ALL patients with prominent IL-7R-JAK1/3-STAT5 activity.
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Project description:STAT5 Gain-of-Function Mutations Promote Precursor T-Cell Receptor Activation to Drive Immature T-Lymphoblastic Leukemia or Lymphoma
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Project description:Transcriptional profiling of mouse osteoclasts comparing control osteoclasts from Stat5 flox mice with osteoclasts from Stat5 cKO mice. Two-condition experiment, Stat5 flox cells vs. Stat5 cKO cells
2013-12-09 | E-GEOD-51283 | biostudies-arrayexpress
Project description:Recurrent gain-of-function mutations in the transcription factor STAT5 have been detected in PTCL, an aggressive, heterogeneous disease, for which currently no targeted therapy exists. Here we investigated whether constitutive activation of STAT5 suffices to drive PTCL and whether inhibition of the JAK/STAT pathway offers a novel therapeutic opportunity in this disease. We found pronounced STAT5 expression and activity in patients from different PTCL subsets. To mimic high STAT5 activity we expressed a hyperactive STAT5A variant (termed vcS5) in the hematopoietic lineage in transgenic mice. vcS5-transgenic animals developed a lethal PTCL-like disease with full penetrance, characterized by massive expansion of CD8+ T-cells and destructive organ-infiltration. Adoptive transfer of vcS5-expressing CD8+ T-cell rapidly induced the disease in immunocompetent recipient mice. Neoplastic vcS5-T-cells displayed cytokine-hypersensitivity and showed activated, memory CD8+ T-lymphocyte characteristics. Histo-pathological analysis as well as mRNA expression profiles of vcS5 mice was closely correlated with distinct human lymphoma subtypes, including PTCL. Treatment of murine and human PTCL cell lines with the clinical JAK inhibitor Ruxolitinib or a selective STAT5 SH2 domain inhibitor induced cell death. Thus, our results demonstrate that enhanced STAT5 signaling drives PTCL development and suggest inhibition of the JAK/STAT5 pathway as a valuable therapeutic option for patients suffering from these aggressive lymphomas.
2017-10-18 | GSE74176 | GEO
Project description:The NUP214-ABL1 fusion is a constitutively activated tyrosine kinase that is significantly associated with overexpression of the TLX1 or TLX3 transcription factors in T-cell acute lymphoblastic (T-ALL). Here we show that NUP214-ABL1 kinase cooperates with TLX1 in driving T-ALL development using a transgenic mouse model. Using ChIP-seq and ATAC-seq, we show that TLX1 and STAT5, the downstream effector of NUP214-ABL1, selectively increase the accessibility of enhancer regions, and cooperatively activate the expression of key proto-oncogenes such as MYC and BCL2. Moreover, MYC is also part of the TLX1/STAT5 complex and inhibition of both MYC and STAT5 leads to reduction of target gene expression.
2018-06-26 | GSE102209 | GEO
Project description:STAT5 is critical for differentiation, proliferation and survival of progenitor B cells suggesting a possible role in Acute Lymphoblastic Leukemia (ALL). Herein, we show increased expression of activated STAT5 in ALL patients, which correlates with treatment outcome. Mutations in Ebf1 and Pax5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1 but this had little affect on most EBF1 or PAX5 target genes. However, a subset of these genes was deregulated and included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL. Gene expression profiling was performed on cells isolated from lymph nodes of Stat5b-CA x Ebf1+/- and Stat5b-CA x Rag2-/- leukemic mice and pre B cells sorted from bone marrow of C57BL/6 mice and Stat5b-CA transgenic mice. 17 Samples.
2011-05-09 | E-GEOD-25645 | biostudies-arrayexpress
Project description:STAT5 is critical for differentiation, proliferation and survival of progenitor B cells suggesting a possible role in Acute Lymphoblastic Leukemia (ALL). Herein, we show increased expression of activated STAT5 in ALL patients, which correlates with treatment outcome. Mutations in Ebf1 and Pax5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1 but this had little affect on most EBF1 or PAX5 target genes. However, a subset of these genes was deregulated and included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL.
2011-05-09 | GSE25645 | GEO
Project description:Transcriptional profiling of mouse osteoclasts comparing control osteoclasts from Stat5 flox mice with osteoclasts from Stat5 cKO mice.
2013-12-09 | GSE51283 | GEO