Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas

• Published in: Blood Vol. 105; no. 7; pp. 2916 - 2923
• Main Authors: Muris, Jettie J.F., Cillessen, Saskia A.G.M., Vos, Wim, van Houdt, Inge S., Kummer, J.Alain, van Krieken, Johan H.J.M., Jiwa, N.Mehdi, Jansen, Patty M., Kluin-Nelemans, Hanneke C., Ossenkoppele, Gert J., Gundy, Chad, Meijer, Chris J.L.M., Oudejans, Joost J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.04.2005; The Americain Society of Hematology
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 3; Caspase 8; Caspase 9; Caspases - metabolism; Chemotherapy; Etoposide - administration & dosage; Female; Hematologic and hematopoietic diseases; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - mortality; Lymphoma, B-Cell - pathology; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - mortality; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction - physiology; Treatment Outcome; X-Linked Inhibitor of Apoptosis Protein; Antineoplastic agent; Human; Immunohistochemistry; Treatment resistance; Lymph node; Enzyme; Cysteine endopeptidases; Malignant hemopathy; B-Lymphocyte; Large cell lymphoma; Non Hodgkin lymphoma; Lymphoma; Peptidases; Anatomic pathology; Chemotherapy; Treatment; Signaling pathway; Lymphoproliferative syndrome; Primary; Hydrolases; Predictive factor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-07-2716

We used biopsy specimens of primary nodal diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular FLICE inhibitory protein (c-Flip) and numbers of active caspase 3-positive lymphoma cells were used to determine the status of the caspase 8-mediated pathway. Expression levels of Bcl-2 and X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a caspase 8 inhibition profile, one with caspase 8 and 9 inhibition profiles, and one with a caspase 9 inhibition profile. Caspase 9 inhibition was strongly associated with poor response to chemotherapy and usually with fatal outcome, whereas caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the caspase 9-mediated pathway, but not the caspase 8-mediated pathway, is a major cause for therapy resistance in patients with nodal DLBCL.