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Targeting canonical and non-canonical STAT3 signaling by WB737, a novel potent STAT3 inhibitor, in natural killer/T-cell lymphoma

ABSTRACT: Targeting canonical and non-canonical STAT3 signaling by WB737, a novel potent STAT3 inhibitor, in natural killer/T-cell lymphoma

PROVIDER: PRJNA837858 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19187868_1.fastq.gz	Fastqsanger.gz
	SRR19187868_2.fastq.gz	Fastqsanger.gz
	SRR19187869_1.fastq.gz	Fastqsanger.gz
	SRR19187869_2.fastq.gz	Fastqsanger.gz
	SRR19187870_1.fastq.gz	Fastqsanger.gz

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Targeting canonical and non-canonical STAT3 signaling by WB737, a novel potent STAT3 inhibitor, in natural killer/T-cell lymphoma

Project description:Activating mutations of STAT3 were frequently found in patients with natural killer/T-cell lymphoma (NKTL), suggesting that targeted inhibition of STAT3 is a potential therapeutic option for NKTL patients. Here, we have developed a novel and potent STAT3 inhibitor WB737 that directly binds to the STAT3-SH2 domain with high affinity. WB737 selectively inhibits cell growth of NKTL harbored STAT3 mutations through inducing apoptosis and blocking colony formation. Mechanistically, WB737 inhibits both canonical and non-canonical STAT3 signaling via suppression of STAT3 phosphorylation at Tyr705 and Ser727 sites, respectively. Moreover, the activity of WB737 has a more potent inhibition on STAT3 compared to Sttatic, resulting in a significant anti-tumor effect followed by almost complete tumor regression in a NKTL xenograft model harboring STAT3 activating mutation. Collectively, these findings provide a preclinical proof-of-concept for WB737 as a novel therapeutic strategy for the treatment of NKTL patients with STAT3-activating mutations.

2023-06-21 | GSE202944 | GEO

Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma

Project description:The transcription factors STAT3, STAT5A and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promotes acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for STAT3/5 targeted therapy. We evaluated JPX‑0700 and JPX-0750 efficacy as dual STAT3/5 binding inhibitors promoting protein degradation. JPX‑0700/-0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in survival, proliferative or epigenetic-modifier STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated in mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.

2024-12-10 | GSE263984 | GEO

Natural killer cell proliferation requires canonical IRE1 function during viral infection

Project description:Natural killer cell proliferation requires canonical IRE1 function during viral infection

| PRJNA992477 | ENA

Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma.

Project description:Natural killer/T-cell lymphoma (NKTL) is an uncommon malignancy with poor prognosis and limited therapeutic options. Activating mutations of signal transducer and activator of transcription 3 (STAT3) are frequently found in patients with NKTL, suggesting that targeted inhibition of STAT3 is a potential therapeutic option for this disease. Here, we have developed a small molecule drug WB737 as a novel and potent STAT3 inhibitor that directly binds to the STAT3-Src homology 2 domain with high affinity. In addition, the binding affinity of WB737 to STAT3 is 250-fold higher than STAT1 and STAT2. Interestingly, WB737 is more selective for NKTL with STAT3-activating mutations in terms of growth inhibition and apoptotic induction when compared with Stattic. Mechanistically, WB737 inhibits both canonical and noncanonical STAT3 signaling via suppression of STAT3 phosphorylation at Tyr705 and Ser727, respectively, thereby inhibiting the expression of c-Myc and mitochondria-related genes. Moreover, WB737 inhibited STAT3 more potently than Stattic, resulting in a significant antitumor effect with undetectable toxicity, followed by almost complete tumor regression in an NKTL xenograft model harboring a STAT3-activating mutation. Taken together, these findings provide preclinical proof-of-concept for WB737 as a novel therapeutic strategy for the treatment of NKTL patients with STAT3-activating mutations.

| S-EPMC10274570 | biostudies-literature

Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma

Project description:Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma

| PRJNA1100503 | ENA

Natural killer cell proliferation requires canonical IRE1 function during viral infection (RNA-Seq)

Project description:Natural killer cell proliferation requires canonical IRE1 function during viral infection (RNA-Seq)

| PRJNA992481 | ENA

Natural killer cell proliferation requires canonical IRE1 function during viral infection (CITE-Seq)

Project description:Natural killer cell proliferation requires canonical IRE1 function during viral infection (CITE-Seq)

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IL-6/Stat3-Dependent Induction of Distinct, Obesity-Associated Natural Killer Cells Deteriorates Energy and Glucose Homeostasis

Project description:Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance. We demonstrate that in mice obesity promotes the expansion of interleukin-6 receptor (IL6Ra)-expressing NK cells, which also express a number of other myeloid lineage genes such as the colony-stimulating-factor 1 receptor (Csf1r). Selective ablation of Csf1r- expressing NK cells prevents obesity and insulin resistance. Moreover, conditional inactivation of IL6Ra or Stat3 in NK cells limits obesity-associated formation of myeloid signature NK cells, protects from obesity, insulin resistance and obesity-associated inflammation. Also in humans IL6Ra+ NK cells increase in obesity, correlate with markers of systemic low-grade inflammation and their gene expression profile overlaps with characteristic gene sets of NK cells in obese mice. Collectively, we demonstrate that obesity-associated inflammation and metabolic disturbances depend on IL-6/Stat3-dependent formation of distinct NK cells, which may provide a novel target for the treatment of obesity, metaflammation-associated pathologies and diabetes.

2017-07-05 | GSE99068 | GEO

Non-canonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

Project description:Non-canonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

2020-07-01 | GSE151447 | GEO

Expression profiling of Natural killer B cells

Project description:Investigation of global gene expression levels between B cells, Natural killer cells and Natural killer B cells Gene expression profiling using sorted B cells, Natural killer cells and Natural killer B cells from WT mouse spleen. Total RNA extracted from WT cells were quantified by the NanoDrop ND-1000 and RNA integrity was assessed by standard denaturing agarose gel electrophoresis. The sample preparation and microarray hybridization were performed based on the NimbleGenâs standard protocols.

2016-05-17 | E-GEOD-80063 | biostudies-arrayexpress

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