STAT3 mutation

The first-line treatment for LGL leukemia is historically based on immunosuppressive agents (methotrexate, cyclophosphamide, or cyclosporine). However, cytokines blocking molecules or Jak/STAT inhibitors represent a new conceptual therapeutic approach for LGL leukemia. In this review, we present an overview of the spectrum of LGL proliferations, potential links between LGL expansion and autoimmunity, and therapeutic approaches.

We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. Both JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.

Altogether, we conclude that the blockade of the JAK2/STAT3/BCL-2 antiapoptotic signaling axis is a vital mechanism whereby CTS provokes bladder cancer cytotoxicity. The current evidence implicates CTS's potential to be translated into a bladder cancer therapeutic agent.

CH + /LGLL cases also showed a higher progression rate to MN than CH-/LGLL (10% vs. 2% at 5 years; P = 0.02). A close relationship between CH and LGLL suggests that cytopenia in LGLL may be not only related to LGLL but be also secondary to coexisting clonal cytopenia of unclear significance.

STAT3 activating mutations were detected in RA patient CD8+ cells and associated with seropositivity. Thus, STAT3 activating mutations may play a role in disease pathogenesis in a subset of RA patients.

Large granular lymphocytes and T-cell receptor rearrangement were detected, thus leading to the diagnosis of T-LGLL and PRCA. This is the first documented case of PBL with T-LGLL and PRCA, offering insight into PBL's pathophysiology and the complications of PBL.

Gene expression profiling data have shownthat ALK-negative ALCL has distinctive molecular signatures, different from ALK+ ALCL and other T-cell lymphomas. Better understanding of the morphologic, immunophenotypic, genetic and molecular features of ALK-negative ALCL will help establish the correct diagnosis, guide therapeutic strategies and improve patient outcomes.

STAT3 mutation is present in various MNs, but not in MPN. It is often an early event or occurs upon leukemic transformation, suggesting an important role in the pathogenesis and progression of MNs by activating JAK-STAT pathway. It may help identify a subset of patients with MNs who may benefit from targeted therapy.

Indeed, NSCLC cells expressing the STAT3 mutant which R609 was replaced to alanine (R609K) show significantly impaired tumour growth in nude mice. Overall, our study reveals a mechanism by which STAT3 remains activated in NSCLC and provides a new target for cancer therapeutic approaches.

Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

The current treatment is based on immunosuppressive therapies, which frequently produce unsatisfactory long-term responses, and for this reason, personalized approaches and targeted therapies are needed. Here, we discuss molecular pathogenesis, clinical presentation, associated autoimmune disorders, and the available treatment options, including emerging therapies.

We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.

Mechanistically, Fucoxanthin targets the JAK2/STAT3/BCL-xL antiapoptotic axis to provoke melanoma cell death. This discovery implicates the potential application of Fucoxanthin as a chemopreventive or therapeutic strategy for melanoma management.

To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, a ligand to cereblon in E3 ubiquitin ligase complex, to generate a proteolysis-targeting chimera (STAT3DPROTAC)...Finally, local C-STAT3DPROTAC administration to human Ly3 lymphoma-bearing mice triggered tumor regression, while control C-STAT3D and C-SCR treatments had limited effects. Our results underscore the feasibility of using a PROTAC strategy for cell-selective, decoy oligonucleotide-based STAT3 targeting of and potentially other tumorigenic transcription factors for cancer therapy.

In conclusion, our findings shed light on the unique molecular complexity of PBL, unveiling its mutational landscape and potential therapeutic targets. Due to the rarity of PBL, further research with a more extensive sample size is essential to completely elucidate the mutational landscape of PBL.

It is demonstrated that C21orf58 displays an oncogenic role in promoting cell growth, tumorigenesis and sorafenib resistance of HCC cells by abnormal activation of STAT3 signaling...Moreover, it is validated that inhibition of C21orf58 with drug alminoprofen, selected by virtual screening, could effectively repress the viability and tumorigenesis of HCC cells. Therefore, it is identified that C21orf58 functions as an oncogenic adaptor, reveal a novel regulatory mechanism of JAK2/STAT3 signaling, explain the cause of abnormal activity of activated mutants of STAT3, and explore the attractive therapeutic potential by targeting C21orf58 in HCC.

Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57 CD8 T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57 CD8 T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes.

Overall, this review sheds light on the intricate relationships between inflammation and cancer, emphasizing the importance of the STAT3 gene and its activation in the pathophysiology of these conditions. Gaining a deeper understanding of these underlying mechanisms seeks to pave the way for the development of novel targeted therapies for patients affected by inflammation-related cancers.

Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.

Deletion of chromosome 13q14 was frequent. The PBL cases in Taiwan showed recurrent mutations involving JAK-STAT, RAS-MAPK, epigenetic regulation, and NOTCH signaling pathways, findings similar to that from the West.

Honokiol was also confirmed to significantly prolong the survival of mice bearing xenograft tumors in a PIAS3-dependent fashion. Together, these findings highlight a novel pathway through which Honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation and promoting the apoptotic death of tumor cells.

Thus, our studies provide a high-resolution transcriptome atlas of breast epithelial cells of BRCA1 and BRCA2 mutation carriers and reveal their susceptibility to PIK3CA mutation-driven transformation.  .

First line single agent therapy with methotrexate (MTX), cyclosporine, and cyclophosphamide have shown similar overall response rates of 40-50%, though STAT3 mutated disease is associated with better response to MTX...Our patient was initiated on prednisone, though due to poor tolerance was transitioned to MTX titrated to 12...The same study found better responses to cyclosporine as first line therapy, an interesting observation as MTX has been generally accepted as first line therapy based on predominantly retrospective studies, though these studies did not stratify treatment responses by TCR phenotype. These findings underscore the need for prospective studies characterizing Tγδ specific disease course, survival analyses and treatment response.

In comparisons with the inoculation of STAT3-KD cells reconstituted with wild-type STAT3, the inoculation of STAT3-KD cells reconstituted with the K685R mutant significantly enhanced tumorigenesis and hepatosplenomegaly in nude mice. Collectively, these results revealed for the first time that the acetylation of STAT3 at K685 attenuated NPM-ALK-induced oncogenesis.

The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy.

Other first-line treatments and their corresponding median duration of response (months) included cyclosporine (n=7, 72 months), cyclophosphamide (n=5, 72 months), IVIG (n=1, 16 months), and methotrexate (n=11, 21 months). Subsequent lines of therapy included campath (n=9), cyclosporine (CSA) (n=4), cyclophosphamide (n=9), intravenous immunoglobulin (IVIG) (n=2), MTX (n=4), rituximab (n=1), sirolimus (n=1), tacrolimus (n=2), and tofacitinib (n=2)...These significant findings contribute substantially to advancing our comprehension of LGLL-associated HA and its optimal management strategies. AIHA in patients with LGLL points towards a global immune dysfunction in this disease beyond clonal cytotoxic T/NK cell expansion.

Most common second line therapy was Ciclosporin (22.3%) followed by Cyclophosphamide (4%), Sirolimus (2.7%) and Anti-Thymocyte Globulin (1.33%)...Other therapies received were IVIG, erythropoietin and disease-directed therapy,e.g lenalidomide for MDS with 5q- and thymectomy...Response to initial therapy was seen in the majority of idiopathic PRCA patients, however response was lower in patients with an underlying malignancy. Of note we identified STAT3 mutations in two patients, highlighting the role of molecular testing and keeping a broad differential diagnosis when presented with this rare condition.

The initial dose of cyclophosphamide and prednisone were 100mg/day and 0.5-1mg/kg/day, respectively...The complete response rate (CRR) [31% (5/16) vs 33% (19/58), P=0.909] and overall response rate (ORR) [56% (9/16) vs 50% (29/58), P=0.658] of cyclosporine (CsA) treatment were similar in patients with STAT3 mutations or not...Leukemia. 2020, 34: 1116–1124.

Commonly used agents include low doses of methotrexate or cyclophosphamide. Ruxolitinib induced durable responses in pts with LGL and therefore may represent an option for pts requiring treatment. STAT3 mutation status was predictive of EFS and responses were associated with JAK/STAT pathway down-regulation, demonstrating on-target effects. Integrated immune profiling suggests that ruxolitinib may interrupt JAK/STAT-dependent paracrine inflammatory signals that promote bone marrow suppression.

P2, N=28, Recruiting, John Reneau | Not yet recruiting --> Recruiting

Collectively, we conclude that MHME provokes TNBC cell apoptosis through the blockade of the SRC/STAT3/BCL-2 pro-survival axis. Our findings suggest the potential of applying MHME as a TNBC chemotherapy agent.

5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate...We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/β-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.

Current treatment using immunosuppressive doses of methotrexate, cyclophosphamide, or cyclosporine A has modest efficacy, and the responses are usually not durable. No new safety signal was observed. The study is actively recruiting at Moffitt Cancer Center, Tampa, FL.

Additionally, TET2-only mutated T-LGLL (n = 5) had a significant reduction in platelet values compared with the WT (n = 16) or STAT3-only mutated T-LGLL (n = 12) (p < 0.05). In conclusion, we compared the somatic mutational landscape between STAT3/STAT5B WT and mutated patients and correlate with their distinct clinical characteristics.

Overall, the current study indicated sertindole exerts bladder cancer cytotoxicity by provoking apoptosis through targeted inhibition of the antiapoptotic STAT3/BCL-xL signaling axis. These findings implicate the potential to repurpose sertindole as a therapeutic strategy for bladder cancer.

The results suggest that STAT3 mutations are significantly less common in FS than in RA-associated T-LGL leukaemia. Moreover, NGS can detect clones undetectable by fragment analysis. We speculate that in patients with RA and neutropenia, the detection of STAT3 mutations can point to T-LGL leukaemia even in the absence of clonal TCR rearrangement.

Our results also highlight that there are monoclonal T-LGL cells with or without STAT3 mutations that cause symptoms such as neutropenia on one end of a spectrum and reactive oligoclonal T-LGL lymphoproliferations on the other. Longitudinal analysis revealed temporal clonal dynamics and showed that T-LGL cells might arise as an epiphenomenon when co-occurring with other malignancies, possibly reactive toward tumor antigens.

Moreover, T-LGLL patients' monocytes showed abnormal activation of signaling pathways, further supporting the different pathogenetic role of monocytes in patients with discrete clinical settings. Altogether, our data contribute to deepen the knowledge on the different cell subtypes in TLGLL, particularly focusing on non-leukemic cell populations and thus offering the rationale for new therapeutic strategies.

Next-generation sequencing revealed a STAT3 mutation, commonly detected in BIA-ALCL, and a unique KRAS mutation reported for the first time in this lymphoma type. Both JAK/STAT3 and RAS/MEK/ERK oncogenic pathways were activated in BIA-XR1, which are targetable with clinically available agents.