Oncotarget

Research Papers:

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder

Claudia Walliser, Martin Wist, Elisabeth Hermkes, Yuan Zhou, Anja Schade, Jennifer Haas, Julia Deinzer, Laurent Désiré, Shawn S.C. Li, Stephan Stilgenbauer, Joshua D. Milner and Peter Gierschik _

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Oncotarget. 2018; 9:34357-34378. https://doi.org/10.18632/oncotarget.26173

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Abstract

Claudia Walliser1, Martin Wist1, Elisabeth Hermkes1, Yuan Zhou1, Anja Schade1, Jennifer Haas1, Julia Deinzer1, Laurent Désiré2, Shawn S.C. Li3, Stephan Stilgenbauer4, Joshua D. Milner5 and Peter Gierschik1

1Institute of Pharmacology and Toxicology, Ulm University Medical Center, Ulm 89070, Germany

2Diaxonhit, Paris 75013, France

3Department of Biochemistry and The Siebens-Drake Medical Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5C1, Canada

4Department of Internal Medicine III, Ulm University Medical Center, Ulm 89070, Germany

5Laboratory 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-γ2 (PLCγ2) 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 PLCγ2-associated antibody deficiency and immune dysregulation, APLAID, respectively. The functional relationships of the PLCγ2S707Y mutation to other PLCG2 mutations causing (i) Btk inhibitor resistance of CLL cells and (ii) the APLAID-related human disease PLCγ2-associated antibody deficiency and immune dysregulation, PLAID, revealing different clinical characteristics including cold-induced urticaria, respectively, are currently incompletely understood. Here, we show that PLCγ2S707 point mutants displayed much higher activities at 37° C than the CLL Btk inhibitor resistance mutants R665W and L845F and the two PLAID mutants, PLCγ2Δ19 and PLCγ2Δ20-22. Combinations of CLL Btk inhibitor resistance mutations synergized to enhance PLCγ2 activity, with distinct functional consequences for different temporal orders of the individual mutations. Enhanced activity of PLCγ2S707Y was not observed in a cell-free system, suggesting that PLCγ2 activation in intact cells is dependent on regulatory rather than mutant-enzyme-inherent influences. Unlike the two PLAID mutants, PLCγ2S707Y 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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