Nfatc1/Αa and Blimp-1 Support the Follicular and Effector Phenotype of Tregs

CD4 + CXCR5 + Foxp3 + T follicular regulatory (T FR ) cells control the germinal center responses. Like follicular helper T-cells, they express high levels of N uclear F actor of A ctivated T -cells c1 , predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of T FR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a T FR migrates into the GC and how effectively it controls antibody production. NFATc1/αA is necessary to overcome T FR -expressed B l ymphocyte- i nduced m aturation p rotein (Blimp-1), which can directly repress Cxcr5. Blimp-1…

EZH2 mutations are frequent and represent an early event in follicular lymphoma

Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harbori…

Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1

Abstract Richter’s transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase–associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurren…

FIRST-LINE THERAPY OF T-CELL LYMPHOMA: ALLOGENEIC OR AUTOLOGOUS TRANSPLANTATION FOR CONSOLIDATION - FINAL RESULTS OF THE AATT STUDY

NFATc1 affects mouse splenic B cell function by controlling the calcineurin–NFAT signaling network

Mouse B cells lacking NFATc1 exhibit defective proliferation, survival, isotype class switching, cytokine production, and T cell help.

RSPO2 gene rearrangement – a new cancer driver in the liver

Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays

Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays

Transmission of angioimmunoblastic T-cell lymphoma by bone marrow transplant

Accidental transmission of lymphoma by bone marrow transplant is a rarely reported event [1–5], since candidates are only accepted for hematopoietic stem cell donation after a work-up that routinel...

Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas

AbstractIntegrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them w…

Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS‐1)

Thymomas are thymic epithelial neoplasms, associated with a variety of autoimmune disorders (especially myasthenia gravis), that apparently result from aberrant intra-tumourous thymopoiesis and export of inefficiently tolerized T-cells to the periphery. The autoimmune regulator (AIRE) drives the expression of self-antigens in the thymic medulla and plays an essential role in ‘central’ tolerance in both humans and mice. However, while inactivating AIRE mutations result in the ‘autoimmune polyendocrinopathy syndrome type 1’ (APS-1), its major features are not well reproduced in AIRE-knock-out mice. Therefore, alternative human disease scenarios with concomitant AIRE deficiency may be valuable…

B-MIND: MOR208 plus bendamustine (BEN) versus rituximab (RTX) plus BEN in patients with relapsed or refractory (R-R) diffuse large B-cell lymphoma (DLBCL): An open-label, randomized phase II/III trial.

TPS7571 Background: Patients ineligible for stem cell transplantation (SCT) or who relapse after SCT, and those who fail to respond to second-line or salvage chemotherapy, represent an unmet medical need for which new therapeutic strategies are required. MOR208 is a novel Fc-enhanced, humanized, monoclonal antibody directed against CD19. Significant single-agent activity of MOR208 in patients with R-R DLBCL (Jurczak et al., J Clin Oncol 34, 2016 [suppl; abstr 7545]) and enhancement of MOR208-mediated cytotoxicity by BEN in preclinical studies, provide a strong rationale to study MOR208 + BEN in patients with R-R DLBCL. Methods: B-MIND is a randomized (1:1), two-arm, multicenter, open-label…

RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

ObjectiveWe aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC).DesignLarge cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in ß-catenin-activated HCA (b-HCA) and HCC with at least moderate nuclear CTNNB1 accumulation. Ultra-deep sequencing was used to characterise CTNNB1wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed.ResultsA roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microd…

Thymic Hyperplasia with Lymphoepithelial Sialadenitis (LESA)-Like Features: Strong Association with Lymphomas and Non-Myasthenic Autoimmune Diseases.

Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32&ndash

MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma

The MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30% of cases of mucosa-associated lymphoid tissue (MALT) lymphoma. Here, we show that deregulated MALT1 expression may occur in B-cell non-Hodgkin lymphoma (B-NHL) of various histologic subtypes either through translocation to the immunoglobulin heavy chain (IGH) locus or by genomic amplification. First, 2 cases, one case of MALT lymphoma and another of aggressive marginal zone lymphoma (MZL) with t(14;18)(q32;q21), cytogenetically identical to the translocation involving BCL2, were shown by fluorescence in situ hybridization (FISH) to involve MALT1, which lies about 5 Mb centromeric of BCL2. Molecular cloni…

Selective loss of regulatory T cells in thymomas

Myasthenia gravis (MG) is the prime autoimmune manifestation of thymomas. We investigated the generation of T cells with a regulatory phenotype (T(R)) in thymomas with and without associated MG. In patients with MG(+) thymomas, maturation and export of T(R) cells but not of other T-cell subsets was significantly reduced. We conclude that imbalance between effector and regulatory T cells in thymomas may be involved in modulation of onset and/or severity of MG.

Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity

A novel transgenic mouse, in which the transcription factor NFATc1 bears lysine-to-arginine mutations that prevent modification by SUMO, develops normally and is healthy. However, SUMO-insensitive NFATc1 transmits strong tolerogenic signals, thus preventing autoimmune and alloimmune T cell responses.

Clinicogenetic Risk Models in Patients Randomized to Receive Consolidative Autologous Stem-Cell Transplantation after Frontline R-CHOP for Advanced Follicular Lymphoma: An Analysis from the GLSG2000 Trial

Abstract Introduction: Advanced follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. About 20% of patients have early progression of disease (POD) and short overall survival (OS). We have previously shown that integration of lymphoma-specific gene mutations and clinical factors improves pretreatment risk stratification (Pastore, 2015) and prediction of early POD (i.e., within 24 months, POD24; Jurinovic, 2016). Recently, we have shown that high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is an effective treatment option for eligible patients with high-risk disease as defined by POD24 (Jurinovic, 2018). Here, we aimed to explore wheth…