The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of Silvestrol and related compounds. For example, eIF4A promotes T-ALL development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with Silvestrol has powerful therapeutic effects in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5′UTR sequences such as the 12-mer guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and Silvestrol-sensitive transcripts are a number of oncogenes, super-enhancer associated transcription factors, and epigenetic regulators. Hence, the 5′UTRs of selected cancer genes harbour a targetable requirement for the eIF4A RNA helicase.

Myostatin is a secreted protein that normally functions as a negative regulator of muscle growth. Agents capable of blocking the myostatin signaling pathway could have important applications for treating human muscle degenerative diseases as well as for enhancing livestock production. Here we describe a potent myostatin inhibitor, a soluble form of the activin type IIB receptor (ACVR2B), which can cause dramatic increases in muscle mass (up to 60% in 2 weeks) when injected into wild-type mice. Furthermore, we show that the effect of the soluble receptor is attenuated but not eliminated in Mstn ؊/؊ mice, suggesting that at least one other ligand in addition to myostatin normally functions to limit muscle growth. Finally, we provide genetic evidence that these ligands signal through both activin type II receptors, ACVR2 and ACVR2B, to regulate muscle growth in vivo. Mice carrying a targeted mutation in the myostatin gene have muscles that are about twice the normal size as a result of a combination of muscle fiber hyperplasia and hypertrophy (2). Myostatin appears to play a similar role in other species as well; naturally occurring mutations in the myostatin gene have been shown to be responsible for the double-muscling phenotype in cattle (3-6), and recent studies have demonstrated that a human baby with approximately twice the normal muscle mass is also homozygous for a loss-of-function mutation in the MSTN gene (7). These findings have raised the possibility that agents capable of targeting the myostatin signaling pathway may be useful for increasing muscle mass for both agricultural and human therapeutic applications. In this regard, loss of myostatin signaling has been shown to have beneficial effects in mouse models of muscle degenerative (8, 9) and metabolic (10) diseases.Various myostatin-binding proteins have been identified that are capable of inhibiting myostatin activity in vitro (8,(11)(12)(13)(14)(15)(16). Two of these proteins, the JA16 neutralizing monoclonal antibody (Ab) directed against myostatin (8, 15) and a mutant form of the myostatin propeptide resistant to members of the BMP-1͞tolloid family of metalloproteases (16), have been shown to be capable of increasing muscle mass by Ϸ25% when administered to wild-type (WT) mice. To determine whether these increases in muscle growth are the maximal achievable by targeting this signaling pathway, we sought additional myostatin inhibitors that might have a broader specificity in their ability to target additional members of the TGF-␤ superfamily. Previous studies have demonstrated that myostatin is capable of binding the two activin type II receptors, ACVR2B and, to a lesser extent, ACVR2, in transfected COS cells (11,17). Moreover, transgenic mice in which a myosin light chain promoter͞ enhancer was used to express a truncated form of ACVR2B in skeletal muscle were found to have dramatic increases in muscle mass (11). Because the activin type II receptors have been shown to be capable of binding a number of other TGF-␤ family members in addition to ...

The lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). However, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center (GC) involution, impedes B cell differentiation and class switch recombination (CSR). Integrative genomic analyses indicate that KMT2D affects H3K4 methylation and expression of a specific set of genes including those in the CD40, JAK-STAT, Toll-like receptor, and B cell receptor pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3, and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell activating pathways.

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The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM deficient lymphoma B cells also induce a tumor supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T Lymphocyte Attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202)) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development and our study illustrates the use of CAR-T cells as ‘micro-pharmacies’ able to deliver an anti-cancer protein.