Peripheral T-cell lymphomas (PTCLs) are mature T-cell and natural killer (NK) cell neoplasms with poor prognosis and no available standard treatment. The 2016 revision of the World Health ...Organization classification of hematological malignancies recognized a new group of nodal T-cell lymphoma with T follicular helper cell phenotype due to the presence of a group of PTCLs, not otherwise specified. This new subgroup of tumors showed clinical and molecular similarities with angioimmunoblastic T-cell lymphoma (AITL). AITL patients have mutations in the Vav guanine nucleotide exchange factor-1 (VAV1) gene. We established a transgenic mouse model harboring VAV1 gene mutation. These mice developed tumors that mimic human T-lymphoblastic lymphoma and the newly proposed PTCL-GATA3 subtype. To develop personalized treatment strategies by analyzing subgroup-specific mouse models, our study supports the establishment of PTCL subgroups based on genetic alterations or gene expression profiles.
Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss‐of‐function TET2 mutations are frequently ...observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2‐deficient immune cells in tumor tissues. Myeloid‐specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single‐cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2‐deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2‐deficient mice relative to controls. Finally, treatment of Tet2‐deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2‐mutated clonal hematopoiesis.
Our study suggests that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis. We present evidence that signaling through the S100a8/S100a9‐Emmprin‐Vegfa axis is essential for progression of a lung cancer model established in a microenvironment of Tet2‐deficient immune cells. Furthermore, we provide a novel target for lung cancer patients with accompanying TET2‐mutated clonal hematopoiesis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) includes various diseases. Attempts have been made to identify distinct properties of disease within the PTCL, NOS classification and ...evaluate their significance to prognosis. Comprehensive gene expression analysis and evaluation of genomic abnormalities have successfully identified specific diseases from heterogeneous PTCL, NOS cases. For example, cases with properties of T follicular helper cells have been identified and classified as an entity resembling angioimmunoblastic T-cell lymphoma (AITL), based on both immunohistochemistry and genomic features. Here, we focus on the molecular pathology of PTCL, NOS and discuss recent changes relevant to its classification.
Angioimmunoblastic T‐cell lymphoma (AITL) is an age‐related malignant lymphoma, characterized by immune system‐dysregulated symptoms. Recent sequencing studies have clarified the recurrent mutations ...in ras homology family member A (RHOA) and in genes encoding epigenetic regulators, tet methyl cytosine dioxygenase 2 (TET2), DNA methyl transferase 3 alpha (DNMT3A) and isocitrate dehydrogenase 2, mitochondrial (IDH2), as well as those related to the T‐cell receptor signaling pathway in AITL. In this review, we focus on how this genetic information has changed the understanding of the developmental process of AITL and will in future lead to individualized therapies for AITL patients.
Recent progress in next‐generation sequencing has revealed the AITL specific genomic abnormalities in epigenetic regulators and TCR signaling. In this paper, we focused on the insights on how the biological and clinical aspects are linked to the genomic features of AITL.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Model Predictive Control (MPC) is one of the effective control methods for complex systems such as automatic driving and robotics. As one of the MPC solvers, the cross-entropy method (CEM) is well ...known as the most flexible and general method. Although CEM can be applied to most systems, it requires a sufficient (theoretically infinite) number of samples and updates for convergence, resulting in extremely high computational cost. Therefore, we focus on the asymmetry of the Kullback-Leibler divergence used in the minimization problem of CEM, and propose a new algorithm for CEM by redefining its minimization problem, so-called risk aversion CEM (RA-CEM). RA-CEM allows the function that can be regarded as a weight for the sampled trajectory to take negative values, so that even with a small iteration, the algorithm actively avoids trajectories with poor performance and prioritizes convergence to trajectories with good performance. In a highway driving simulation, RA-CEM improved the success rate from the standard CEM.
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) includes various diseases. Attempts have been made to identify distinct properties of disease within the PTCL, NOS classification and ...evaluate their significance to prognosis. Comprehensive gene expression analysis and evaluation of genomic abnormalities have successfully identified specific diseases from heterogeneous PTCL, NOS cases. For example, cases with properties of T follicular helper cells have been identified and classified as an entity resembling angioimmunoblastic T-cell lymphoma (AITL), based on both immunohistochemistry and genomic features. Here, we focus on the molecular pathology of PTCL, NOS and discuss recent changes relevant to its classification.
Immunoglobulin (Ig) heavy/light chain (HLC) assays enable the separate quantification of the different light chain types of each Ig class. We retrospectively analyzed the correlation of heavy/light ...chain ratio (HLCR) with clinical status and its impact on outcome in 120 patients with multiple myeloma (MM). Abnormal HLCR was seen more frequently in patients with poorer myeloma response, and it appeared to be more sensitive for detecting clonality in IgA myeloma compared to IgG myeloma after treatment. Among the 85 patients who achieved ≥VGPR, the patients remained HLCR abnormal were showed significantly shorter overall survival (OS) compared to those achieving a normal HLCR (not reached vs 55.5 months, P = 0.032). This correlation was seen in IgA myeloma patients (not reached vs 30.1 months, P = 0.014), but not in IgG myeloma patients when patients were analyzed separately. Univariate and multivariate analysis of factors that may affect survival identified abnormal HLCR at the best response as the only independent risk factor (hazard ratio, 4.7; 95% confidence interval, 1.4 – 15.26; P = 0.012) for shorter OS in this subset of patients. This study highlighted the HLC assay as a prognostic predictor in patients with IgA myeloma.
Immunoglobulin heavy/light chain (HLC) assay is a newer assay which can measure the different light chain types of each Ig class separately. To investigate the clinical utility of HLC assay, we measured HLC and FLC in relation to the IMWG responses in patients with IgG and IgA myeloma after treatment and evaluated its prognostic relevance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Angioimmunoblastic T‐cell lymphoma (AITL) is a subtype of nodal peripheral T‐cell lymphoma (PTCL). Somatic RHOA mutations, most frequently found at the hotspot site c.50G > T, p.Gly17Val (G17V RHOA ...mutation) are a genetic hallmark of AITL. Detection of the G17V RHOA mutations assists prompt and appropriate diagnosis of AITL. However, an optimal detection method for the G17V RHOA mutation remains to be elucidated. We compared the sensitivity and concordance of next‐generation sequencing (NGS), droplet digital PCR (ddPCR) and peptide nucleic acid‐locked nucleic acid (PNA‐LNA) clamp method for detecting the G17V RHOA mutation. G17V RHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA‐LNA clamp method both detected G17V mutations in 4 samples in addition to those detected with NGS (31 of 67, 46.3%). Additionally, variant allele frequencies with ddPCR and those with NGS showed high concordance (P < .001). Three other RHOA mutations involving the p.Gly17 position (c.49G > T;50G > T, p.Gly17Leu in PTCL198; c.50G > T;51A > C, p.Gly17Val in PTCL216; and c.50G > A, p.Gly17Glu in PTCL223) were detected using NGS. These sequence changes could not appropriately be detected using the ddPCR assay and the PNA‐LNA clamp method although both indicated that the samples might have mutations. In total, 34 out of 67 PTCL samples (50.7%) had RHOA mutations at the p.Gly17 position. In conclusion, our results suggested that a combination of ddPCR/PNA‐LNA clamp methods and NGS are best method to assist the diagnosis of AITL by detecting RHOA mutations at the p.Gly17 position.
Angioimmunoblastic T‐cell lymphoma (AITL) is a distinct subtype of nodal peripheral T‐cell lymphoma (PTCL). Somatic RHOA mutations, (most frequently c.G50T, p.G17V RHOA mutation) are a genetic hallmark of AITL. Our results showed that a combination of NGS, ddPCR and PNA‐LNA clamp methods increased the detection rate of RHOA mutations at the p.G17 position.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•ACH-derived GCB cells with aberrant expression profiles underwent independent clonal evolution in the microenvironment of AITL.•Inhibition of the CD40–CD40LG axis, as revealed by in silico network ...analysis, is a potential novel therapeutic target.
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Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas the G17V RHOA mutation in immature cells with TET2 mutations promotes the development of T follicular helper (TFH)-like tumor cells. Here, we investigated the mechanism by which TET2-mutant immune cells enable AITL development using mouse models and human samples. Among the 2 mouse models, mice lacking Tet2 in all the blood cells (Mx-Cre × Tet2flox/flox × G17V RHOA transgenic mice) spontaneously developed AITL for approximately up to a year, while mice lacking Tet2 only in the T cells (Cd4-Cre × Tet2flox/flox × G17V RHOA transgenic mice) did not. Therefore, Tet2-deficient immune cells function as a niche for AITL development. Single-cell RNA-sequencing (scRNA-seq) of >50 000 cells from mouse and human AITL samples revealed significant expansion of aberrant B cells, exhibiting properties of activating light zone (LZ)-like and proliferative dark zone (DZ)-like germinal center B (GCB) cells. The GCB cells in AITL clonally evolved with recurrent mutations in genes related to core histones. In silico network analysis using scRNA-seq data identified Cd40–Cd40lg as a possible mediator of GCB and tumor cell cluster interactions. Treatment of AITL model mice with anti-Cd40lg inhibitory antibody prolonged survival. 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.
The second most common peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), arises from T-follicular helper cells in the context of age-related clonal hematopoiesis. Fujisawa and colleagues utilized single cell analyses of primary samples and murine models to reveal that TET methylcytosine dioxygenase 2 (TET2) mutations within clonal B cells in the tumor microenvironment are necessary for facilitating TET2-mutated AITL. Their data also suggest a novel therapeutic possibility.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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