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

Depending on its occurrence in the germline or somatic context, a single point mutation, S707Y, of phospholipase C-γ (PLCγ) 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-associated antibody deficiency and immune dysregulation, APLAID, respectively. The functional relationships of the PLCγS707Y mutation to other mutations causing (i) Btk inhibitor resistance of CLL cells and (ii) the APLAID-related human disease PLCγ-associated antibody deficiency and immune dysregulation, PLAID, revealing different clinical characteristics including cold-induced urticaria, respectively, are currently incompletely understood. Here, we show that PLCγS707 point mutants displayed much higher activities at 37° C than the CLL Btk inhibitor resistance mutants R665W and L845F and the two PLAID mutants, PLCγΔ19 and PLCγΔ20-22.

The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein.

Mutations in the gene encoding phospholipase C-γ (PLCγ) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib. The fact that two of these mutations, R665W and L845F, imparted upon PLCγ an ∼2-3-fold ibrutinib-insensitive increase in the concentration of cytosolic Ca following ligation of the B cell antigen receptor (BCR) led to the assumption that the two mutants exhibit constitutively enhanced intrinsic activity. Here, we show that the two PLCγ mutants are strikingly hypersensitive to activation by Rac2 such that even wild-type Rac2 suffices to activate the mutant enzymes upon its introduction into intact cells.

Implications for the usage of the left lateral liver graft for infants ≤10 kg, irrespective of a large-for-size situation--are monosegmental grafts redundant?

Organ donor shortage for infant liver transplant recipients has lead to an increase in splitting and living donation. For cases in which even transplantation of the left lateral graft (Couinaud's segments II + III) results in a "large for size situation" with an estimated graft body weight ratio (GBWR) of >4%, monosegmental liver transplantation was developed. This, however, bears complications because of greater parenchymal surface and suboptimal vascular flow.