scholarly journals Ripk3 Signaling Restricts the Development of Peripheral T Cell Lymphoma in Tet2 Deficient Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3318-3318
Author(s):  
Kanak Joshi ◽  
Ryan Mack ◽  
Lei Zhang ◽  
Shanhui Liu ◽  
Mark Sellin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
T Helper Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Wild Type ◽  
T Helper ◽  
Peripheral T Cell Lymphoma ◽  
Helper Cells

Abstract Inactive mutations of the Ten-eleven translocation (TET2) gene are commonly found in humans with multiple hematological malignancies including myeloproliferative neoplasm (MPN), acute myeloid leukemia, diffuse large B cell lymphoma, and peripheral T cell lymphomas (PTCL), and are frequently associated with poor prognosis and worse overall survival. TET2 mutations often occur in hematopoietic stem and progenitor cells (HSPCs) and are known to collaborate with additional mutations for full-blown malignant transformation. However, the molecular mechanism by which the disease identity is determined remains to be elucidated. Increased inflammatory cytokines are commonly detected in patients with TET2 mutations, which is associated with an increased risk of atherosclerotic cardiovascular diseases. Most Tet2 knockout (Tet2 -/-) mice develop MPN-like disease within 18 months, with only a few cases developing chronic lymphocyte leukemia-like disease at two years of age. The intestinal bacteria-induced inflammatory signaling plays a critical role in the pathogenesis of MPN-like disease in Tet2 -/- mice. Receptor-interacting protein kinase 3 (Ripk3) is a key mediator of inflammation cytokine-induced necroptosis and metabolic signaling. Compared to bone marrow (BM) cells isolated from wild-type mice, higher levels of Ripk3 activity can be detected in Tet2 -/- BM cells. To study the role of Ripk3 in Tet2 mutations associated with hematopoietic diseases, we crossed Tet2 conditional knockout (Tet2fx/fx Mx1-Cre +) mice with Ripk3 -/- mice to generate Tet2 and Ripk3 compound knockout (Tet2 -/-Ripk3 -/-) mice. Tet2 -/-Ripk3 -/- mice developed aggressive tumors by 12-15 months of age as characterized by profound hepatosplenomegaly and lymphadenopathy, with substantial lymphocytosis, neutrophilia, anemia, and thrombocytopenia. Histopathological analysis revealed an aggressive infiltration of tumor cells in the liver and spleen, and effacement of splenic follicular structures in diseased Tet2 -/-Ripk3 -/- mice. To characterize the type of malignancies, single-cell suspensions of the BM, peripheral blood (PB), and spleen from Tet2 -/-Ripk3 -/- were analyzed by flow cytometry and compared with wild-type and Tet2 -/- mice. As expected Tet2 -/- mice exhibited increased frequencies of myeloid cells in the PB, BM, and spleen. However, there was a marked expansion of CD4 + T cells in the PB, BM, and spleen of Tet2 -/-Ripk3 -/- mice. Detailed analyses of the T subsets demonstrated a marked expansion of both CD4 +PD1 +CXCR5 + follicular T helper cells (T fh) and CD4 +PD1 + peripheral T helper cells (T ph), indicating the development of a peripheral T cell lymphoma (PTCL) in the Tet2 -/-Ripk3 -/- mice. Additionally, disease characteristics including the reduced surface expression of CD3 in the tumor cells, increased levels of classical T h cytokines in the serum, as well as the presence of heterogeneous populations of cells within the tumor tissues recapitulate the pathological features of angioimmunoblastic T cell lymphoma (AITL), a subtype of PTCL. Elevated frequencies of splenic T fh and T ph cells were detected as early as 7 months of age in Tet2 -/-Ripk3 -/- mice. Such cells expressed inducible T cell costimulatory receptor (ICOS), an essential signaling mediator of the T fh development and proliferation. However, all other hematopoietic parameters including BM HSPCs and mature CD4 + T cells were comparable to wild type and single-gene Tet2 -/- mice. These results indicate that Ripk3 signaling inhibits PTCL development in Tet2 -/- mice by limiting the expansion of T fh and T ph cells. We are currently determining whether Ripk3 plays such a role by inducing necroptosis and/or restricting the differentiation of CD4 + naive T cells into peripheral T fh and T ph populations. We are also investigating whether Ripk3 signaling is inactivated in the tumor cells of human PTCL patients and whether we can treat such aggressive fatal diseases by reactivating Ripk3 signaling. Disclosures No relevant conflicts of interest to declare.

scholarly journals Angioimmunoblastic T cell lymphoma is derived from mature T-helper cells with varying expression and loss of detectable CD4

2002 ◽  
Vol 103 (1) ◽  
pp. 12-20 ◽  
Author(s):  
Seung-Sook Lee ◽  
Thomas Rüdiger ◽  
Tobias Odenwald ◽  
Sabine Roth ◽  
Petr Starostik ◽  
...  
Keyword(s):  
T Cell ◽  
T Helper Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
T Helper ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Helper Cells

Evaluation of follicular T-helper cells in primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma and dermatitis

2013 ◽  
Vol 40 (12) ◽  
pp. 1006-1013 ◽  
Author(s):  
Mina S. Ally ◽  
Ranganna Y. Prasad Hunasehally ◽  
Manuel Rodriguez-Justo ◽  
Blanca Martin ◽  
Roberto Verdolini ◽  
...  
Keyword(s):  
T Cell ◽  
T Helper Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
T Helper ◽  
Helper Cells ◽  
Follicular T Helper Cells

scholarly journals Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells?

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1501-1502 ◽  
Author(s):  
Karen L. Grogg ◽  
Ayoma D. Attygalle ◽  
William R. Macon ◽  
Ellen D. Remstein ◽  
Paul J. Kurtin ◽  
...  
Keyword(s):  
T Cell ◽  
Germinal Center ◽  
T Helper Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
T Helper ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Helper Cells

Peripheral T-cell Lymphoma, NOS With Epstein-Barr Virus Positivity in an Elderly Patient With Myelodysplastic Syndrome: An Autopsy Case Report

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S81-S81
Author(s):  
J Lanceta ◽  
W Xue ◽  
M Hurford ◽  
H Wu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Barr Virus ◽  
Epstein Barr

Abstract Casestudy Epstein-Barr virus (EBV)-associated peripheral T-cell lymphomas are a group of aggressive neoplasms with a geographic predilection for South America and Asia, but are very rare in Western populations. Results We report a case of a 74-year-old Caucasian female who presented with pancytopenia and B symptoms with EBV-IgG detected on admission. Past medical history included: ITP, chronic urticaria, and recently diagnosed myelodysplastic syndrome (MDS) on bone marrow biopsy one month prior to admission. Excisional biopsies of an enlarged right neck lymph node (repeated within 6 months) and right axillary lymph node five years ago were negative for a lymphoproliferative disorder at the time. Repeated bone marrow biopsy, performed during the current admission, confirmed the diagnosis of MDS, with scattered T-cells without aberrant immunophenotype. Despite aggressive treatment from multiple specialties, the patient deteriorated and expired four weeks later from complications of MDS. At autopsy, there was diffuse lymphadenopathy involving the mediastinum, axilla, pelvis and peripancreatic fat. Lymph node sections demonstrated nodal architecture effacement by diffuse, vaguely nodular lymphoid infiltrates. Histologically, the infiltrates were composed of medium to large lymphocytes with round to slight irregular nuclei, rare Reed-Sternberg-like multinucleated cells, clumped chromatin, and indistinct nucleoli. Individual cell necrosis was abundant with mitotic figures readily identifiable. Immunohistochemistry revealed CD2+ CD3+ neoplastic T-cells that co-express MUM1 and a subset of CD30, while negative for CD4, CD5, CD8, CD56, ALK1, and TDT. EBV-encoded RNA in-situ hybridization was focally positive. The final postmortem diagnosis was peripheral T-cell lymphoma, not otherwise specified (NOS), with focal EBV positivity. Conclusion Co-existence of a de-novo MDS and non-Hodgkin lymphoma without any prior chemotherapeutic exposure is a highly unusual finding, although MDS-like presentations can occur with EBV-associated lymphomas. Peripheral T-cell lymphoma, NOS is an aggressive lymphoma and EBV positivity has been found correlated with a poor prognosis. This case demonstrates how postmortem examination remains an important tool in clinical- pathological correlation and highlights the potential pathogenetic role EBV plays in MDS and T-cell lymphoma.

scholarly journals Neonatal lymphocyte subpopulations analysis and maternal preterm premature rupture of membranes: a pilot study

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Margherita Amadi ◽  
Silvia Visentin ◽  
Francesca Tosato ◽  
Paola Fogar ◽  
Giulia Giacomini ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Helper Cells ◽  
Lymphocyte Subpopulations ◽  
T Helper ◽  
Premature Rupture Of Membranes ◽  
Premature Rupture ◽  
Preterm Premature Rupture ◽  
Helper Cells

Abstract Objectives Preterm premature rupture of membranes (pPROM) causes preterm delivery, and increases maternal T-cell response against the fetus. Fetal inflammatory response prompts maturation of the newborn’s immunocompetent cells, and could be associated with unfavorable neonatal outcome. The aims were to examine the effects of pPROM (Mercer BM. Preterm premature rupture of the membranes: current approaches to evaluation and management. Obstet Gynecol Clin N Am 2005;32:411) on the newborn’s and mother’s immune system and (Test G, Levy A, Wiznitzer A, Mazor M, Holcberg G, Zlotnik A, et al. Factors affecting the latency period in patients with preterm premature rupture of membranes (pPROM). Arch Gynecol Obstet 2011;283:707–10) to assess the predictive value of immune system changes in neonatal morbidity. Methods Mother-newborn pairs (18 mothers and 23 newborns) who experienced pPROM and controls (11 mothers and 14 newborns), were enrolled. Maternal and neonatal whole blood samples underwent flow cytometry to measure lymphocyte subpopulations. Results pPROM-newborns had fewer naïve CD4 T-cells, and more memory CD4 T-cells than control newborns. The effect was the same for increasing pPROM latency times before delivery. Gestational age and birth weight influenced maturation of the newborns’ lymphocyte subpopulations and white blood cells, notably cytotoxic T-cells, regulatory T-cells, T-helper cells (absolute count), and CD4/CD8 ratio. Among morbidities, fewer naïve CD8 T-cells were found in bronchopulmonary dysplasia (BPD) (p=0.0009), and more T-helper cells in early onset sepsis (p=0.04). Conclusions pPROM prompts maturation of the newborn’s T-cell immune system secondary to antigenic stimulation, which correlates with pPROM latency. Maternal immunity to inflammatory conditions is associated with a decrease in non-major histocompatibility complex (MHC)-restricted cytotoxic cells.

scholarly journals Genome-Wide microRNA Expression Profiling in Molecular Subgroups of Peripheral T-Cell Lymphoma Identified Role of Mir-126 in T-Cell Lymphomagenesis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2767-2767
Author(s):  
Waseem Lone ◽  
Alyssa Bouska ◽  
Tyler Herek ◽  
Catalina Amador ◽  
Mallick Saumyaranajn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Ectopic Expression ◽  
T Cell Lymphoma ◽  
Molecular Subgroups ◽  
Peripheral T Cell Lymphoma ◽  
Tfh Cells

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas and approximately 30% of PTCLs are designated as not-otherwise specified (PTCL-NOS). Gene expression profiling (GEP) identified molecular classifiers for PTCL entities and identified 2 novel biological subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21), associated with T-cell differentiation subsets. To further investigate molecular oncogenesis, we performed microRNA expression profiling (miR-EP) in several molecular subtypes of PTCL including angioimmunoblastic T-cell lymphoma (AITL), PTCL-GATA3 and PTCL-TBX21 using formalin fixed paraffin embedded tissues. We also performed miR-EP of normal T-cell subsets polarized to represent different differentiation stages (TFH, TH1 and TH2). We performed miR-EP on 102 PTCL cases using either quantitative real time PCR (ABI, Biosystem) or ultra-sensitive direct miRNA counting (nCounter, NanoString). Corresponding GEP (mRNA) were available for 67 PTCL cases. Normal T-cells were polarized in-vitro with different cytokine milieu and examined by flow cytometry. We observed distinct miRNA profiles, with miRNA being uniquely expressed in TFH polarized cells (miR-26a-5p, miR-17-5p, miR-30d-5p, miR-22-3p, miR-222-3p, miR-142-3p, let-7i-5p and miR-29b-3p). In contrast, the TH1 lineage was enriched for expression of miR-155-5p, miR-146a-5p, miR-1246, miR-93-5p, miR-16-5p, miR-21-5p, miR-363-3p, miR-1260a, miR-186-5p, miR-148a-3p and miR-579-3p, whereas TH2 polarized cells expressed miR-181a-5p, let-7a-5p, miR-191-5p, miR-15b-5p, let-7d-5p, let-7b-5p, miR-140-5p, miR-98-5p, miR-423-5p and miR-630. Several of these miRNA expressed in the T-cells subsets showed corresponding expression in their respective PTCL entity such as miR-142-3p, let7i-5p, miR-21-5p and miR-29b-3p with AITL, miR-146-5p, miR-155-5p and miR-16-5p in PTCL-TBX21 and miR-181a-5p, miR-630 and let7a-5p in PTCL-GATA3. We also performed the MiRNA Enrichment Analysis and Annotation (miEAA) for miRNA signatures and observed an enrichment of miRNA regulating epigenetic modifications in TFH cells (p=0.028), whereas TH1 showed an enrichment of miRNA regulating IFN-g signaling (p=0.0024), and miRNA signatures in TH2 showed negative regulation of TGF-b signaling (p=0.023). Supervised analysis (p=0.05) of the miRNA profiles identified significant association of miR-126, miR-145, and let-7c-5p with AITL, when compared to other PTCLs. Similarly, miR-92a, miR-25, miR-636, miR-210, miR-222 and miR-491-5p significantly associated with PTCL-GATA3 and miRNA 126-3p, 145-5p, miR-26a-5p and miR-34a-5p associated with PTCL-TBX21. The miEAA for tumor miRNA signatures revealed enrichment of miRNAs regulating histone methylation (h3 k4 methylation) and chemokine receptor signaling in AITL, whereas miRNA regulating T-cell receptor were enriched in PTCL-TBX21 and TP53 signaling pathway in PTCL-GATA3. We validated the expression of miR-126 in AITL by qRT-PCR and also observed its increased expression in IL21 stimulated CD4+ T-cells. Ectopic expression of miR-126 resulted in a ~3 fold increased expression in T-cell lines and led to reduced proliferation and increased apoptosis with expression of T-cell exhaustion makers PD1 and TIM3. Computational algorithmic programs identified relevant biological targets of miR-126, including p85/PIK3R2, S1PR2 and DNMT3A that were further validated in-vitro. We observed an inverse correlation of miR-126 expression with S1PR2 expression (r=-0.64). S1PR2 is a crucial G protein-coupled receptor regulating B and T-cell migration in the germinal center (GC) reaction. Migration assays demonstrated significant decreases in T to B-cell migration, when B-cells (Raji) were co-cultured with Jurkat cells with ectopic expression of miR-126. With the GC reaction holding an important role in AITL, we investigated the biological significance of miRNA-126 in the context of the AITL microenvironment. High expression of miRNA-126 significantly associated with inferior survival in AITL (p=0.008) and significant differences in tumor microenvironment signatures. We identified distinct miRNA signatures for AITL and molecular subgroups of PTCL-NOS. Furthermore, elevated expression of miR-126 may contribute to the dysregulation and the homing of TFH cells in GC reaction through S1PR2 and warrants further mechanistic investigation. Disclosures No relevant conflicts of interest to declare.

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