SGK1 mutations in DLBCL generate hyperstable protein neoisoforms that promote AKT independence

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Serum and glucocorticoid-regulated kinase 1 (SGK1) is frequently mutated in diffuse large B-cell lymphoma (DLBCL).
• Previous studies assumed SGK1 mutations represent loss-of-function, implicating SGK1 as a tumor suppressor in DLBCL.
• The precise function of SGK1 and the consequences of its mutation in DLBCL remain poorly understood.

Purpose of the Study:

• To investigate the functional consequences of common SGK1 mutations in DLBCL.
• To challenge the prevailing hypothesis of SGK1 as a tumor suppressor in DLBCL.
• To explore the therapeutic potential of targeting SGK1 in DLBCL.

Main Methods:

• Analysis of SGK1 mutations and their effect on mRNA splicing and protein expression in DLBCL cells.
• Assessment of the kinase activity of SGK1 protein isoforms.
• Evaluation of cellular response to AKT inhibition in the presence of altered SGK1 expression.
• Investigation of downstream signaling pathways, including GSK3B phosphorylation.

Main Results:

• The most common SGK1 mutations in DLBCL result in aberrantly spliced mRNA and N-terminally truncated protein isoforms.
• These truncated SGK1 isoforms exhibit increased expression due to the exclusion of an N-terminal degradation domain.
• Overexpression of functional SGK1 kinase domain confers resistance to AKT inhibition by increasing GSK3B phosphorylation.

Conclusions:

• SGK1 mutations in DLBCL do not lead to loss of function but rather to increased expression of active kinase isoforms.
• These findings challenge the current view of SGK1 as a tumor suppressor in DLBCL.
• Pharmacological inhibition of SGK1 represents a potential therapeutic strategy for DLBCL treatment.