Avery, Danielle A, Kane, Elisa, Nguyen, Tina, Lau, Anthony, Nguyen, Akira, Payne, Kathryn, Lenthall, Ellen, Wei, Shi, Brigden, henry, French , Elise, Bier, Julia, Hermes, Jana R, Zahra, David, Sewell, William, Boztug, Kaan, Meyts, Isabelle, Choo, Sharon, Hsu, Peter, Wong, Melanie, Berglund, Lucinda, Gray, Paul, O'Sullivan, Michael, Cole, Therese, Holland, Steven M, Ma, Cindy S, Burkhart, Christoph, Corcoran, Lynn M, Phan, Tri G, Brink, Robert, Uzel, Gulbu, Deenick, Elissa K and Tanguye, Stuart G (2018) Pathogenic germline activating mutations in PIK3CD intrinsically compromise B-cell development and function, underlying humoral defects in human primary immunodeficiency. Journal of Experimental Medicine.

Abstract

By analysing a large cohort of patients with activating mutations in PIK3CD, and developing a novel mouse model of Pik3cdGOF by CRISPR/Cas9-mediated genome editing, we have now revealed key functions for PI3K in B-cell development and differentiation. B cell development in human BM was perturbed at the pre-BII and immature stages, with an aberrant accumulation of these cells and corresponding reductions in recirculating mature B cells. The study has provided insight into the pathophysiology of PIK3CD GOF mutations. Furthermore, our observations that the Pik3cdE1020K mutation in murine B cells mirrored the effects of PIK3CD GOF mutations in humans underscores the utility of this mouse model to investigate the consequences of hyper-active PI3K signaling, and dissect mechanisms of disease pathogenesis in humans with corresponding mutations. Thus, these mice will be a valuable pre-clinical model to screen new or alternative pharmacological or biological inhibitors or the PI3K pathway as novel therapeutics for humans with PIK3CD GOF mutations.

Item Type:	Article
Date Deposited:	01 Aug 2018 00:45
Last Modified:	01 Aug 2018 00:45
URI:	https://oak.novartis.com/id/eprint/35042