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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.

oncotarget

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