RHOA G17V

The wild-type blocking technologies that have been reported to overcome this include blocker displacement amplification (BDA), non-extendable locked nucleic acid (LNA), hot-spot-specific probes (HSSP), etc. These technologies use specific oligonucleotide sequences to block wild-type or recognize wild-type and then combine this with other methods to prevent wild-type amplification and amplify mutant amplification, leading to characteristics like high sensitivity, flexibility, and convenience. This protocol uses BDA, a wild-type blocking PCR combined with Sanger sequencing, to optimize the detection of RHOA G17V low-frequency somatic mutations, and the detection sensitivity can reach 0.5%, which can provide a basis for MRD monitoring of angioimmunoblastic T-cell lymphoma.

Our case demonstrates a plausible correlation between the diagnosis of AITL following mRNA vaccination due to the malignant transformation of the TFH cells in patients who have a predisposing mutation of RHOA-17v. Given the rarity of AITL and the heterogeneity of molecular findings, more studies are needed to establish such an association.

We described a series of 15 well-characterized TFHL patients with an indolent outcome, suggesting that a watch-and-wait approach can be proposed in selected patients. Identifying factors predicting such evolution is warranted.

Concurrent nodal involvement by AITL and KS is rare and identification of both neoplastic components may pose diagnostic challenges. The question of whether the association between AITL and KS may be fortuitous or could reflect the underlying immune dysfunction in AITL remains open.

Low mRNA expression of PHLPP2 predicted poor prognosis (p=.03) and engineered PHLPP2 loss showed enhanced PI(3)K activation and FOXO1 inactivation in CD4+ T-cells in-vitro. Thus, we defined the genomic landscape for AITL, which is largely characterized by epigenetic alterations, TCR signaling and PI3K/AKT dysregulation, which may be amenable for therapeutic targeting.

Particularly, we identified the molecular subgroup with unfavorable prognosis (A53) for which different clinical approach should be warranted. This classification will refine the patient prognostication and stratification in nTFHL.

Collectively, these findings reveal an unexpected role for RHOA G17V in potentiating CD28 T195P-induced NFAT transcriptional activity through the modulation of p300 HAT activity and expand the notion that epigenetic deregulation contributes to the pathogenesis of TFH lymphomas. Our results suggest that targeting p300 acetyltransferase activity may open new avenues for TFH lymphoma therapies.

Accordingly, we observed a significant negative correlation between the relative area of collagen in histological sections from 18 primary AITL and the allele frequency of the RHOA-G17V mutation. In conclusion, our results suggest that the characteristic presentation of AITL with early, widespread dissemination of lymphoma cells is not the result of an enhanced migration capacity due to the RHOA-G17V mutation; instead, this feature may rather be related to extracellular matrix remodelling.

These two immunocompetent cases of nTFHL with EBV-positive tumour cells exhibit the featured gene mutation profile and poor prognosis of this disease. This novel finding of EBV positivity in our cases expands the currently recognised spectrum of EBV-positive nodal T cell lymphomas to include rare cases of nTFHL.

New drugs, such as hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDAi), have been used for relapsed/refractory (R/R) disease with promising results. Such agents have their use based on a biological rationale, have significant potential to improve the outcomes of patients with AITL and may represent a paradigm shift in the therapeutic approach to this lymphoma in the near future.

Although not specific for AITL, RHOAG17V mutation shows an association with diagnosis and requires sensitive methods for detection due to low-tumor burden. The mutant status of AITL could have prognostic implications and translational relevance.

Our results demonstrated a wide spectrum of peripheral B-cell morphologies and immunophenotypes of peripheral B cells in AITL. These findings correspond to dysregulated B-cell immunity and heterogeneous clinicopathological features.

Tumor cells of TFH lymphoma acquired the immunosuppressive signature in the clonal evolution process from the G17V Hetero to Homo. Furthermore, comprehensive immune profiling of TFH lymphoma revealed expansion of cells involved in the immune escape. These results unveiled the enrichment of immune evasive phenotypes in TFH lymphoma and suggested their contribution to treatment resistance in RR patients.

In addition, an abnormality of RHOA G17V mutation and PON2 expression is also detected in patients with AITL. Our findings suggest that PON2 associated with RHOA G17V mutation might control the direction of the molecular agents-based AITL and provide a new therapeutic target in AITL.

The genes expressed in aberrantly expanded GCB cells in murine tumors were also broadly expressed in the B-lineage cells of TET2-mutant human AITL. Therefore, ACH-derived GCB cells could undergo independent clonal evolution and support the tumorigenesis in AITL via the CD40-CD40LG axis.

Patients with pcTFH-PTCL have pathological and genetic features that overlap with those of systemic lymphoma of TFH derivation. Clinically, most remained confined to the skin, with only three patients showing systemic spread and death. Whether pcTFH-PTCL should be integrated as a new subgroup of TFH lymphomas in future classifications is still a matter of debate.

PLS3, one of the new tumor markers, could be detected by flow cytometry, a viable method in clinical practice. In the clonal evolution process from the G17V Hetero to Homo, the proliferative signaling switch to the immune escape signaling.

In addition to demonstrating diagnostic challenges, these cases expand the potential of clonal haematopoiesis in the development of different lineage neoplastic proliferations.

In this study, for the first time was demonstrated the unfavorable prognostic impact of the RHOA mutation in patients with nPTCL-Thf (AITL and nPTCL-THf), making it a potential molecular biomarker predictor of poor-PFS, associated with resistance to primary therapy and with high tumor burden. Such results are preliminary and will need to be validated in series with a larger number of cases.

Large cell PTCL-TFH indicated poor prognosis in TFH+ PTCLs. These data suggested that CMYC+ tumour cells and intense PD-L1+ cell reaction influenced tumour cell progression in TFH+ PTCLs, and PD-1+ tumour cell/intense PD-L1+ cell reactions may play a role in immune evasion.

Conclusions Our analyses recapitulate known characteristics of AITL TME, and uncover previously unrecognized heterogeneity among malignant T cells across multiple patients. The distinct gene expression programs, phenotypes, genetics, and locations of T FH -like, T CM -like and CTL-like states suggest that AITL malignant T cells undergo significant functional plasticity and genetic divergence, which could influence response to therapy and overall clinical course.

Furthermore, the AITL-B-specific geneset, which referred from genes ( CD40, CD83, AICDA, MKI67) highly expressed in the GCB cluster in AITLm was enriched not only in the GCB cluster, but also in the naive to memory B clusters in AITLh. Conclusion This study suggests a new concept that ACH-derived GCB cells with TET2 mutations can undergo independent clonal evolution and function as microenvironmental cells to support tumorigenesis in AITL via the CD40-CD40LG axis.

This study demonstrates that priming with oral azacitidine (CC486) in combination with CHOP as initial therapy is safe, effective, and produces sustained remission in PTCL-TFH subtype. Epigenetic priming with azacitidine appears to inhibit the proliferation of TFH lymphoma cells, providing potential synergistic mechanism of action with chemotherapy. This active combination will be further evaluated in the upcoming ALLIANCE/ US Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P vs duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL.

is TET2. There was no statistically significant difference in the frequency distribution of IDH2, DNMT3A and TET2 mutations between the different histological subtypes of nPTCL. However, there was a statistical trend towards a higher occurrence of the RHOA mutation in the AITL and nPTCL-Thf subtypes (3/9–33.3% and 7/16-43.7%, respectively; p = 0.07). So, the RHOA mutation was predominantly found in THf cell-derived neoplasms in our cohort. The mutational status of DNMT3A, RHOA and TET2 genes had no prognostic impact on OS, with p = 0.85, p = 0.13 and p = 0.95, respectively. The same was observed in relation to PFS for the DNMT3A (p = 0.70) and TET2 (p = 0.52) mutations. However, the presence of the RHOA mutation was associated with the unfavorable PFS in our cohort (HR:1.98, p = 0.05). We observed 2-year PFS of 28.6% (95% CI: 8.8-52.4%) for mutated-RHOA cases versus 52.9% (95% CI: 37.3-66.3%) for wild-type-RHOA patients (p = 0.05). We also demonstrated that the presence of the RHOA mutation was a predictor of lower ORR to first-line therapy (p = 0.01) and was associated with high tumor burden (p = 0.03). of the RHOA mutation in patients with nPTCL with THf-phenotype, making it a potential molecular biomarker predictor of poor-PFS, associated with resistance to primary therapy and with high tumor burden.

These observations expand the spectrum of T-cell lymphoma entities that occur in association with CLL/SLL, adding AITL to the rare variants of aggressive neoplasms manifesting as Richter syndrome. Given that disturbances of T-cell homeostasis in CLL/SLL affect not only cytotoxic but also helper T-cell subsets, these may contribute to the emergence of neoplasms of T follicular helper derivation.

This result indicated that our case belonged to a relatively indolent subgroup of nodal peripheral T-cell lymphoma of T phenotype, which affects patients ≤60 years old, recently proposed by our group. This case report expands our understanding of the morphologic spectrum of FTCL and its clinicopathologic significance.

It was observed that the malignant transformation of AITL occurs in a multifactorial process, starting from mutations in lymphoid parents, possibly related to senility, and post-thymic mutations, probably linked to conditions of immune hyperactivity. Despite advances in the biomolecular understanding of the disease, its etiopathogenesis remains unknown.

CYBERSORT analysis of hematopoietic cell populations indicated that treatment with tipifarnib in our mouse lymphoma model is associated with enrichment in NK signatures and a potential decrease of monocytes and neutrophils within the tumor microenvironment. In summary, we have demonstrated that tipifarnib has a strong anti-lymphoma effect on a mouse model of AITL and that this effect might be mediated by the recruitment and/or activation of different hematopoietic cell populations in the tumor microenvironment that can alter the survival and proliferation of lymphoma cells.