STAT5 Gain-of-Function Mutations Promote Precursor T-Cell Receptor Activation to Drive Immature T-Lymphoblastic Leukemia or Lymphoma
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ABSTRACT:
PROVIDER: PRJNA907267 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22478800_1.fastq.gz | Fastqsanger.gz | |||
| SRR22478800_2.fastq.gz | Fastqsanger.gz | |||
| SRR22478801_1.fastq.gz | Fastqsanger.gz | |||
| SRR22478801_2.fastq.gz | Fastqsanger.gz | |||
| SRR22478802_1.fastq.gz | Fastqsanger.gz |
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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.
2024-04-15 | GSE219155 | GEO
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:Hyperactive STAT5 Hijacks T-Cell Receptor Signaling and Drives Immature T-Cell Acute Lymphoblastic Leukemia
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Project description:Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemia stage in which B-cell precursors display self-renewal ability, initiating precursor B-ALL that resembles PAX5 P80R or Ph-like human leukemia. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving both JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are novel treatment avenues for IL-7R-related cases. Our model, a unique resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
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Project description:STAT5 is critical for inducing lineage specifying transcription factors, establishing effector gene programs, upregulating IL-2Rα (also known as CD25), and supporting cell survival in response to environmental cues in mature T cells. Although it has been shown that IL-7-induced STAT5 signaling is also essential for survival of thymic precursor cells, the exact roles of STAT5A and STAT5B and their target genes that contribute to the developmental program in early thymic development have been unknown. To define STAT5 target genes in these early T-cell progenitors, we have performed CRISPR-Cas9 mediated acute deletion of Stat5a and Stat5b in combination. We first carried out preliminary experiments to determine the stages in which IL-7 could induce maximal STAT5 phosphorylation in thymic double negative (DN) cells (B. Shin, unpublished data). We then focused on genes responding to loss of STAT5 in two different stages: CD25+ Bcl11b- pre-commitment stage, and CD25+ Bcl11b+ post-commitment stage. Of note, to generate these early pro-T cells in OP9-DLL1 coculture, we exploited bone-marrow precursor cells expressing a Bcl2 transgene to minimize survival defects due to loss of STAT5A and STAT5B. Our data show that STAT5 is necessary, in both pre- and post-commitment stages, for optimal expression of the IL-2Rα gene (Il2ra), which is constitutively expressed in normal DN2 and DN3 pro-T cells. This dataset further defines a distinct set of additional genes responding more strongly to loss of STAT5 in pro-T cells. The linked manuscript by R. Spolski et al. and other datasets referenced therein include data documenting the genomic occupancy of STAT5B in corresponding stages. In summary, our data define STAT5-responsive target genes during early T development.
2023-10-16 | GSE184845 | 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: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.
2011-05-09 | GSE25645 | GEO
Project description:Human B-cell precursor acute lymphoblastic leukemia cells overexpressing ST6Gal1
| PRJNA770077 | ENA
Project description:T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL) and are often thought to represent a spectrum of a single disease. The malignant cells in T-ALL and T-LL are morphologically indistinguishable, and they share the expression of common cell surface antigens and cytogenetic characteristics. However, despite these similarities, differences in the predominant sites of disease in T-ALL and T-LL are observed. To determine if underlying biological distinctions may potentially contribute to some of these differences, we analyzed the global gene expression profiles of malignant T-cell precursors in ten T-ALL and nine T-LL using DNA arrays. Ten additional B-precursor ALL bone marrow samples, were used in a separate analysis. <br><br> Note that files GSM27087.txt and GSM27088.txt are identical as downloaded from GEO.
2007-08-13 | E-GEOD-1577 | biostudies-arrayexpress