title: Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia.
abstract: Individual cytokines and groups of cytokines that might represent networks in chronic lymphocytic leukemia (CLL) were analyzed and their prognostic values determined. Serum levels of 23 cytokines were measured in 84 patients and 49 age-matched controls; 17 levels were significantly elevated in patients. Unsupervised hierarchical bicluster analysis identified 3 clusters (CLs) of highly correlated but differentially expressed cytokines: CL1 (CXCL9, CXCL10, CXCL11, CCL3, CCL4, CCL19, IL-5, IL-12, and IFNγ), CL2 (TNFα, IL-6, IL-8, and GM-CSF), and CL3 (IL-1β, IL-2, IL-4, IL-15, IL-17, and IFNα). Combination scores integrating expression of CL1/CL2 or CL1/CL3 strongly correlated (P < .005) with time-to-first-treatment and overall survival (OS), respectively. Patients with the worst course had high CL1 and low CL2 or CL3 levels. Multivariate analysis revealed that CL1/CL2 combination score and immunoglobulin heavy chain variable region mutation status were independent prognostic indicators for time-to-first-treatment, whereas CL1/CL3 combination score and immunoglobulin heavy chain variable region mutation status were independent markers for OS. Thus, we identified groups of cytokines differentially expressed in CLL that are independent prognostic indicators of aggressive disease and OS. These findings indicate the value of multicytokine analyses for prognosis and suggest therapeutic strategies in CLL aimed at reducing CL1 and increasing CL2/CL3 cytokines.
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.forename: Igor
authors.initials: I
authors.lastname: Dozmorov
authors.forename: Wentian
authors.initials: W
authors.lastname: Li
authors.forename: Sophia
authors.initials: S
authors.lastname: Yancopoulos
authors.forename: Cristina
authors.initials: C
authors.lastname: Sison
authors.forename: Michael
authors.initials: M
authors.lastname: Centola
authors.forename: Preetesh
authors.initials: P
authors.lastname: Jain
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Sherry
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood; D016022:Case-Control Studies; D054414:Chemokine CCL17 / Q000097:blood; D054371:Chemokine CXCL11 / Q000097:blood; D018925:Chemokines / Q000097:blood / Q000145:classification; D016207:Cytokines / Q000097:blood* / Q000145:classification*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D020381:Interleukin-17 / Q000097:blood; D015848:Interleukin-5 / Q000097:blood; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C106230:CCL17 protein, human; C515202:CXCL11 protein, human; D054414:Chemokine CCL17; D054371:Chemokine CXCL11; D018925:Chemokines; D016207:Cytokines; C508599:IL5 protein, human; D007135:Immunoglobulin Variable Region; D020381:Interleukin-17; D015848:Interleukin-5