Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder
Bibliographic record
Abstract
// Claudia Walliser 1 , Martin Wist 1 , Elisabeth Hermkes 1 , Yuan Zhou 1 , Anja Schade 1 , Jennifer Haas 1 , Julia Deinzer 1 , Laurent Désiré 2 , Shawn S.C. Li 3 , Stephan Stilgenbauer 4 , Joshua D. Milner 5 and Peter Gierschik 1 1 Institute of Pharmacology and Toxicology, Ulm University Medical Center, Ulm 89070, Germany 2 Diaxonhit, Paris 75013, France 3 Department of Biochemistry and The Siebens-Drake Medical Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5C1, Canada 4 Department of Internal Medicine III, Ulm University Medical Center, Ulm 89070, Germany 5 Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20892, USA Correspondence to: Peter Gierschik, email: peter.gierschik@uni-ulm.de Keywords: chronic lymphocytic leukemia; autoinflammation; B cell signaling; Bruton’s tyrosine kinase; inositol phosphates Received: July 18, 2018 Accepted: September 08, 2018 Published: September 28, 2018 ABSTRACT Depending on its occurrence in the germline or somatic context, a single point mutation, S707Y, of phospholipase C-γ 2 (PLCγ 2 ) gives rise to two distinct human disease states: acquired resistance of chronic lymphocytic leukemia cells (CLL) to inhibitors of Brutons´s tyrosine kinase (Btk) and dominantly inherited autoinflammation and PLCγ 2 -associated antibody deficiency and immune dysregulation, APLAID, respectively. The functional relationships of the PLCγ 2 S707Y mutation to other PLCG2 mutations causing (i) Btk inhibitor resistance of CLL cells and (ii) the APLAID-related human disease PLCγ 2 -associated antibody deficiency and immune dysregulation, PLAID, revealing different clinical characteristics including cold-induced urticaria, respectively, are currently incompletely understood. Here, we show that PLCγ 2 S707 point mutants displayed much higher activities at 37° C than the CLL Btk inhibitor resistance mutants R665W and L845F and the two PLAID mutants, PLCγ 2 Δ19 and PLCγ 2 Δ20-22. Combinations of CLL Btk inhibitor resistance mutations synergized to enhance PLCγ 2 activity, with distinct functional consequences for different temporal orders of the individual mutations. Enhanced activity of PLCγ 2 S707Y was not observed in a cell-free system, suggesting that PLCγ 2 activation in intact cells is dependent on regulatory rather than mutant-enzyme-inherent influences. Unlike the two PLAID mutants, PLCγ 2 S707Y was insensitive to activation by cooling and retained marked hyperresponsiveness to activated Rac upon cooling. In contrast to the PLAID mutants, which are insensitive to activation by endogenously expressed EGF receptors, the S707Y mutation markedly enhanced the stimulatory effect of EGF, explaining some of the pathophysiological discrepancies between immune cells of PLAID and APLAID patients in response to receptor-tyrosine-kinase activation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.001 | 0.000 |
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 teacher head, 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".