FOXO1 activation is an effector of SYK and AKT inhibition in tonic BCR signal-dependent diffuse large B-cell lymphomas

Abstract

Inhibition of spleen tyrosine kinase (SYK) in tonic B-cell receptor (BCR) signal-dependent diffuse large B-cell lymphomas (DLBCLs) inhibits cellular proliferation, decreases cholesterol biosynthesis, and triggers apoptosis, at least in part via a mechanism involving decreased activity of phosphatidylinositol 3-kinase/AKT axis. Because forkhead box O1 (FOXO1) is a major effector of this pathway, we investigated the role of FOXO1 in toxicity of BCR pathway inhibition. Inhibition of SYK in DLBCL cells with tonic BCR signaling decreased phospho-AKT and phospho-FOXO1 levels and triggered FOXO1-driven gene expression. Introduction of constitutively active FOXO1 mutant triggered cell cycle arrest and apoptosis, indicating that increased FOXO1 activity is toxic to these DLBCL cells. Depletion of FOXO1 with short hairpin RNA led to almost complete resistance to chemical SYK inhibitor R406, demonstrating that FOXO1 is also required for R406-induced cell death. FOXO1 in these cells is also involved in regulation of expression of the critical master regulator of cholesterol biosynthesis, SREBP1. Because HRK is the key effector of SYK inhibition, we characterized a mechanism linking FOXO1 activation and HRK induction that involves caspase-dependent cleavage of HRK's transcriptional repressor DREAM. Because AKT in lymphoma cells can be regulated by other signals than BCR, we assessed the combined effects of the AKT inhibitor MK-2206 with R406 and found markedly synergistic FOXO1-dependent toxicity. In primary DLBCLs, FOXO1 expression was present in 80% of tumors, correlated with SYK activity, and was associated with longer overall survival. These results demonstrate that FOXO1 is required for SYK and AKT inhibitor-induced toxicity. (Blood. 2016;127(6):739-748)

Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells

“…13,14 FOXO proteins regulate proapoptotic and antiproliferative genes, as well as antioxidant and DNA repair pathways. 15,16 Thus, FOXO1 has tumor-suppressor function in various solid tumors and B-cell lymphomas, [17][18][19][20][21] including Hodgkin lymphoma (HL). 22 Contradictory to these inhibitory effects are recent reports linking high FOXO expression to poor prognosis and tumor-promoting activity in intestinal, neuronal, and hematological malignancies.…”

PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis

“…50, 51 Consequently, upregulation of Bim appears a common mechanism triggered by inhibition of BCR-inducible kinases. Although PI3Kδi-mediated Bim upregulation was evident in vitro in the absence of exogenous antigen, antigen contamination of in vitro cultures from murine tissues is likely.…”

Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration

“…In line with previous reports, CLL cells from our cohort expressed higher levels of all PIM kinase isoforms when compared to healthy B lymphocytes ( Figure S1). Patients with advanced FISHnegative 30 (21) *Number of patients is indicated in parentheses when the entire cohort was not investigated for that variable.…”