PI3Kδ inhibition causes feedback activation of PI3Kα in the ABC subtype of diffuse large B-cell lymphoma.

Georgios N Pongas,Louis M Staudt,Christina M Annunziata

doi:10.18632/oncotarget.20864

Georgios N Pongas, Louis M Staudt + Show 1 more

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https://doi.org/10.18632/oncotarget.20864

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Abstract

Cell line models of the activated B cell-like (ABC) subtype of diffuse large B cell (DLBCL) depend on both NF-κB and phosphatidylinositol 3-kinase (PI3K) signaling pathways for survival, especially those with gain-of-function B cell receptor (BCR) mutations. Here we show that these cells depend specifically on the PI3Kδ isoform, but that PI3K pathway interruption by PI3Kδ inhibitors is short-lived due to feedback activation of the PI3Kα isoform. PI3Kδ and PI3Kα inhibition cooperated in killing ABC DLBCL lines, and genetic knockdown of PI3Kα sensitized cells to PI3Kδ inhibition and prolonged the interruption of PI3K signaling. PI3Kδ inhibition evoked feedback activation of proximal BCR signaling, which increased the association of PI3Kα with BCAP and CD19 and increased overall PI3K activity. These results support the clinical evaluation of dual PI3Kδ and PI3Kα inhibition in patients with ABC DLBCL.

Highlights

Diffuse large B cell lymphoma (DLBCL) is the most common B cell malignancy in the adult population
The B cell receptor (BCR) pathway is known to activate NFκB signaling in activated B cell-like (ABC) DLBCL, we investigated whether combined PI3Kα and PI3Kδ inhibition interferes with NF-κB activation using two complementary assays
A subset of ABC DLBCL lines with BCR mutations are sensitive to pan-phosphatidylinositol 3-kinase (PI3K) inhibitors [8, 11, 21]

Summary

Introduction

Diffuse large B cell lymphoma (DLBCL) is the most common B cell malignancy in the adult population. Gene expression profiling studies defined three types of DLBCL based on cell of origin (COO): the activated B cell-like (ABC) DLBCL, germinal center B cell-like (GCB) DLBCL and primary mediastinal B cell lymphoma (PMBL) [1, 2]. This taxonomy has clinical significance since ABC DLBCL has an inferior prognosis relative to other DLBCLs [3]. One recurrent mechanism to activate NF-κB in ABC DLBCL is chronic active B cell receptor (BCR) signaling [4], which is initiated by self-antigen reactivity of the BCR and is augmented by gain-of-function mutations in the BCR subunits CD79A and CD79B in ~21% of cases [4, 7]. In addition to NF-κB, chronic active BCR signaling in ABC

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