Abstract 3941: Recurrent IL4R mutations in primary mediastinal large B cell lymphoma
Bibliographic record
Abstract
Abstract Introduction: Primary mediastinal large B cell lymphoma (PMBCL) is a distinct subtype of aggressive B cell lymphoma that arises from thymic medullary B cells and characteristically presents as a mass in the anterior mediastinum. A proportion of PMBCL patients suffer from refractory or relapsing disease, and subsequent salvage therapies are frequently ineffective. Development of targeted therapies is impeded by the lack of knowledge about the mutational landscape in the lymphoma genomes and mutation-associated phenotypes. We recently reported somatic mutations in the transcriptome of 7 PMBCL patients and 3 cell lines by next-generation sequencing and found a hotspot mutation in exon 8 of IL4R (Gunawardana et al, Nat Genet, 2014). Interleukin (IL)-4 is a type II cytokine that regulates immune responses through binding to a receptor complex consisting of the IL4 receptor alpha (IL4Rα) chain and IL13Rα or the common gamma chain (γc). Activation of IL4R by IL-4 and/or IL-13 initiates intracellular signal transduction mediated by the phosphorylation of JAnus Kinase-Signal Transducer and Activation of Transcription (JAK-STAT) pathway. We hypothesize that constitutively active JAK-STAT observed in PMBCL is in part due to gain-of-function IL4R mutations signaling through this oncogenic pathway. Methods and samples: A sequencing cohort consisting of fresh-frozen pretreatment lymph node biopsies from 62 PMBCL cases were selected from the BCCA tissue archive. DNA from PMBCL tumors and 3 PMBCL-derived cell lines were extracted for IL4R exonic PCR amplification and Sanger sequencing or high-throughput sequencing on an Illumina MiSeq instrument. WT and mutant (I242N) IL4R cDNA were cloned into mammalian expression vectors and expressed in the lymphoma cell line DEV and in engineered HEK293 cells expressing STAT6. Supernatant from cultured cells were used to measure the activity of STAT6-dependent expression of secreted embryonic alkaline phosphatase (SEAP). Extracted RNA and protein from transfected cells were used for qRT-PCR and Western blotting, respectively. Results: Somatic IL4R mutations were found in 18 of 65 (28%) cases confirming a hotspot mutation (I242N) in exon 8 in 11 of 18 (61%) mutated cases. Ectopic expression of the mutant in HEK293 cells showed increased SEAP levels compared to WT (534% vs. 100%) indicating STAT6 activation independent of cytokine stimulation. Introduction of the mutant into DEV cells showed IL4 independent hyperphosphorylation of JAK2, STAT5 and STAT6 proteins and upregulation of the B cell activation marker CD23 (963% vs. 100% in WT). Conclusions: IL4R is frequently mutated in PMBCL with a recurrent hotspot affecting the transmembrane domain of the protein. Functional analyses characterize these mutations as gain-of-function leading to constitutive activation of the JAK-STAT pathway and downstream target genes. These data suggest IL4R mutations as novel driver alterations in PMBCL and may provide a rational therapeutic target. Citation Format: Jay Gunawardana, Tessa Van Tol, Katina Mak, David Twa, Elizabeth Chavez, Bruce Woolcock, Robert Kridel, Anja Mottok, Shannon Healy, Adele Telenius, Merrill Boyle, Susana Ben-Neriah, Stacy Hung, Christoffer Hother, Randy Gascoyne, Christian Steidl. Recurrent IL4R mutations in primary mediastinal large B cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3941. doi:10.1158/1538-7445.AM2015-3941
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".