title: 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.
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Maciej
authors.initials: M
authors.lastname: Szydlowski
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Kiliszek
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sewastianik
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Ewa
authors.initials: E
authors.lastname: Jablonska
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Emilia
authors.initials: E
authors.lastname: Bialopiotrowicz
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Patryk
authors.initials: P
authors.lastname: Gorniak
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Anna
authors.initials: A
authors.lastname: Polak
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Center-Institute of Oncology, Warsaw, Poland;
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Markowicz
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Center-Institute of Oncology, Warsaw, Poland;
authors.forename: Eliza
authors.initials: E
authors.lastname: Nowak
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Center-Institute of Oncology, Warsaw, Poland;
authors.forename: Monika A
authors.initials: MA
authors.lastname: Grygorowicz
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Monika
authors.initials: M
authors.lastname: Prochorec-Sobieszek
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Anna
authors.initials: A
authors.lastname: Szumera-Cieckiewicz
authors.affiliation: Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; and.
authors.forename: Agata
authors.initials: A
authors.lastname: Malenda
authors.affiliation: Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; and Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Lech-Maranda
authors.affiliation: Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; and.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Warzocha
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D046228:Microarray Analysis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000072377:Syk Kinase; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051057:Proto-Oncogene Proteins c-akt