KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype.

To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.The research was supported by grants from Leukaemia & Lymphoma Research, U.K., Addenbrooke’s Charitable Trust. SM is a PhD student supported by MRC and Department of Pathology, University of Cambridge. LEI is a PhD student supported by the Pathological Society of UK & Ireland. NB is a fellow of the European Hematology Association and was supported by a starter grant from the Academy of Medical Sciences

Significant functional difference between TNFAIP3\small \textit{TNFAIP3} truncation and missense mutants

A20, encoded by TNFAIP3, is a molecular “brake” of the canonical NF-κB activation pathway and attenuates the NF-κB activity triggered by a number of surface receptors.1,2 A20 contains an N-terminal OTU domain that possesses deubiquitinating activity, and 7 zinc finger (ZF) domains in its C-terminus that confers the E3 ubiquitin ligase activity.3 Through removing the K63-linked ubiquitin chain, catalysing the K48-linked polyubiquitination, and also direct binding to the linear polyubiquitin chain of its targets, A20 can inactivate a number of NF-κB positive regulators, including RIP1/2, TRAF6, Ubc13 and NEMO, thus negatively regulating the signalling of several surface receptors, including BCR, TNFR, TLR and IL1βR.1,2,4 A20 itself is a transcriptional target of NF-κB, and its transcriptional activation by NF-κB thus serves as an auto-negative feedback to attenuate NF-κB activities triggered by these receptor signallings.1,2Bloodwise, UK, Addenbrooke’s Charitable Trust, Pathological Society of UK and Irelan

Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-?B, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H(+)-ATP ATPase (V-ATPase) known to be necessary for amino acid-induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting