The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Background Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas. Methods In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety. Results The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%). Conclusions In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.)

Follicular lymphoma (FL) is an incurable malignancy1, with transformation to an aggressive subtype being a critical event during disease progression. Here we performed whole genome or exome sequencing on 10 FL-transformed FL pairs, followed by deep sequencing of 28 genes in an extension cohort and report the key events and evolutionary processes governing initiation and transformation. Tumor evolution occurred through either a ‘rich’ or ‘sparse’ ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histones, JAK-STAT signaling, NF-κB signaling and B-cell development genes. Longitudinal analyses revealed chromatin regulators (CREBBP, EZH2 and MLL2) as early driver genes, whilst mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides novel insights into the genetic basis of follicular lymphoma, the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations within the CPC represents an attractive therapeutic strategy.

The monocarboxylate transporter MCT4 mediates lactic acid efflux from most tissues that are dependent on glycolysis for their ATP production. Here we demonstrate that expression of MCT4 mRNA and protein was increased >3-fold by a 48-h exposure to 1% O 2 , whereas MCT1 expression was not increased. The effect was mimicked by CoCl 2 (50 M), suggesting transcriptional regulation by hypoxia-inducible factor 1␣ (HIF-1␣). The predicted promoters for human MCT1, MCT2, and MCT4 were cloned into the pGL3 vector and shown to be active (luciferase luminescence) under basal conditions. Only the MCT4 promoter was activated (>2-fold) by hypoxia. No response was found in cells lacking HIF-1␣. Four potential hypoxiaresponse elements were identified, but deletion analysis implicated only two in the hypoxia response. These were just upstream from the transcription start site and also found in the mouse MCT4 promoter. Mutation of site 2 totally abolished the hypoxic response, whereas mutation of site 1 only reduced the response. Gel-shift analysis demonstrated that nuclear extracts of hypoxic but not normoxic HeLa cells contained two transcription factors that bound to DNA probes containing these hypoxia-response elements. The major shifted band was abolished by mutation of site 2, and supershift analysis confirmed that HIF-1␣ bound to this site. Binding of the second factor was abolished by mutation of site 1. We conclude that MCT4, like other glycolytic enzymes, is up-regulated by hypoxia through a HIF-1␣-mediated mechanism. This adaptive response allows the increased lactic acid produced during hypoxia to be rapidly lost from the cell.The transport of lactic acid across the plasma membrane is of fundamental importance for all mammalian cells. Glycolytic cells (e.g. white muscle fibers and all cells under hypoxic conditions), must rapidly export lactic acid; other tissues import lactic acid to fuel respiration (brain, heart, and red muscle) or gluconeogenesis (liver and kidney) (1-3). Transport is mediated by a family of proton-linked monocarboxylate transporters (MCT(s)) 2 that are also responsible for the transport of other metabolically important monocarboxylates including the ketone bodies. The MCT family has 14 members (3), 6 of which have been functionally characterized. Of these, only MCT1-MCT4 catalyze proton-coupled transport of lactate (1, 4 -7). MCT1 is expressed in most cells (1, 3), whereas MCT4 is expressed strongly only in glycolytic tissues (e.g. white muscle) that must export large amounts of lactic acid (2, 8). In rats, MCT2 is found in tissues requiring high affinity uptake of lactate or pyruvate such as liver and kidney (both gluconeogenic) and neurons (lactate and pyruvate oxidation). However, MCT2 is absent in most human tissues, whereas MCT3 expression is largely restricted to the retinal pigment epithelium (see Refs. 1 and 3). MCT1, MCT3, and MCT4 require ancillary glycoproteins, either gp70 (Embigin) or, more often CD147 (Basigin), for their expression at the plasma membrane (9 -10). MCT2 does not associ...