Oncogenic Rag GTPase signalling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR

The humoral immune response requires that B cells undergo a sudden anabolic shift and high cellular nutrient levels, which are required to sustain the subsequent proliferative burst. Follicular lymphoma (FL) originates from B cells that have participated in the humoral response, and 15% of FL samples harbour point-activating mutations in RRAGC, an essential activator of mTORC1 downstream of the sensing of cellular nutrients. The impact of recurrent RRAGC mutations in B cell function and lymphoma is unexplored. RRAGC mutations, targeted to the endogenous locus in mice, confer a partial insensitivity to nutrient deprivation, but strongly exacerbate B cell responses and accelerate lymphomagenesis, while creating a selective vulnerability to pharmacological inhibition of mTORC1. This moderate increase in nutrient signalling synergizes with paracrine cues from the supportive T cell microenvironment that activate B cells via the PI3K–Akt–mTORC1 axis. Hence, Rragc mutations sustain induced germinal centres and murine and human FL in the presence of decreased T cell help. Our results support a model in which activating mutations in the nutrient signalling pathway foster lymphomagenesis by corrupting a nutrient-dependent control over paracrine signals from the T cell microenvironment.Research was supported by the RETOS projects Programme of Spanish Ministry of Science, Innovation and Universities, Spanish State Research Agency, cofunded by the European Regional Development Fund (grant SAF2015-67538-R), EU-H2020 Programme (ERC-2014-STG-638891), Excellence Network Grant from MICIU/AEI (SAF2016-81975-REDT), a Ramon y Cajal Award from MICIU/AEI (RYC-2013-13546), Spanish Association Against Cancer Research Scientific Foundation Laboratory Grant, Beca de Investigación en Oncología Olivia Roddom, FERO Grant for Research in Oncology; Miguel Servet Fellowship and Grant Award (MS16/00112 and CP16/00112) and Project PI18/00816 within the Health Strategic Action from the ISCIII (to A.O.-M.), both cofunded by the European Regional Development Fund, Marcos Fernandez Fellowship from the Spanish Leukaemia and Lymphoma Foundation/Vistare Foundation (to A.O.-M.) and L’Oreal For Women in Science Award (to A.O.-M.). J.F. is a recipient of a Cancer Research UK Programme Award (15968) and J.O. is a recipient of a Cancer Research UK Clinician Scientist Fellowship (22742). N.M.-M. is a Ramon y Cajal Awardee MICIU/AEI (RYC-2016-20173). N.D.-S., C.C.A., A.B.P.-G. and K.T. are recipients of Ayudas de contratos predoctorales para la formacion de doctores from MICIU/AEI (BES-2016-077410, BES-2015-073776, BES-2017−081381, BES-2016-078082).Peer reviewe

Impact of the revised (2008) EORTC/MSG definitions for invasive fungal disease on the rates of diagnosis of invasive aspergillosis

Diagnosis of invasive aspergillosis (IA) remains a challenge as the clinical manifestations are not specific, and a histological diagnosis is often unfeasible. The 2002 European Organization for Research and Treatment of Cancer (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria for classification of cases into possible, probable or proven were revised in 2008. Our objective was to analyze the impact of these revisions on the diagnosis of IA. A retrospective analysis of 589 high risk patient-episodes revealed that 125 of 155 'possible' (81%) and 12 of 16 'probable' (75%) cases of IA should be changed to 'non-classifiable' when the new criteria were applied. We concluded, as expected, that the 2008 EORTC/MSG revised definitions reduced the number of cases classified as 'possible' IA, but additionally, there has been a dramatic reduction in 'probable' cases. These changes have significant implications on the interpretation of clinical trial data based on EORTC/MSG classifications

Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma (vol 32, pg 1258, 2018)

International audienc

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 harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy

Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy. © 2014 Nature America, Inc.This study was predominantly funded by Cancer Research UK through the Genomic Initiative and Programme grant (15968) to J.F. and was also supported by Leukemia and Lymphoma Research (grant to J.F.) and Hungarian Scientific Research Fund (Országos Tudományos Kutatási Alapprogramok, OTKA) grant K-76204 (to A.M.). Y.F. is a recipient of the Georgia Cancer Coalition Distinguished Scholar Award, and C.P. and Y.F. are, in part, supported by US National Institutes of Health grant GM085261 (to Y.F.). C.B. is a recipient of the European Hematology Association (EHA) Partner fellowship (2009/1) and was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TÁMOP 4.2.4. A/1-11-1-2012-0001 National Excellence Program. J.O. is a recipient of the Kay Kendall Leukaemia Fund (KKLF) Junior Clinical Research Fellowship (KKL 557)