title: Profiling of apoptosis genes allows for clinical stratification of primary nodal diffuse large B-cell lymphomas.
abstract: Intrinsic resistance of lymphoma cells to apoptosis is a probable mechanism causing chemotherapy resistance and eventual fatal outcome in patients with diffuse large B cell lymphomas (DLBCL). We investigated whether microarray expression profiling of apoptosis related genes predicts clinical outcome in 46 patients with primary nodal DLBCL. Unsupervised cluster analysis using genes involved in apoptosis (n = 246) resulted in three separate DLBCL groups partly overlapping with germinal centre B-lymphocytes versus activated B-cells like phenotype. One group with poor clinical outcome was characterised by high expression levels of pro-and anti-apoptotic genes involved in the intrinsic apoptosis pathway. A second group, also with poor clinical outcome, was characterised by high levels of apoptosis inducing cytotoxic effector genes, possibly reflecting a cellular cytotoxic immune response. The third group showing a favourable outcome was characterised by low expression levels of genes characteristic for both other groups. Our results suggest that chemotherapy refractory DLBCL are characterised either by an intense cellular cytotoxic immune response or by constitutive activation of the intrinsic mediated apoptosis pathway with concomitant downstream inhibition of this apoptosis pathway. Consequently, strategies neutralising the function of apoptosis-inhibiting proteins might be effective as alternative treatment modality in part of chemotherapy refractory DLBCL.
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: J J F
authors.initials: JJ
authors.lastname: Muris
authors.forename: B
authors.initials: B
authors.lastname: Ylstra
authors.forename: S A G M
authors.initials: SA
authors.lastname: Cillessen
authors.forename: G J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: J C
authors.initials: JC
authors.lastname: Kluin-Nelemans
authors.forename: P P
authors.initials: PP
authors.lastname: Eijk
authors.forename: B
authors.initials: B
authors.lastname: Nota
authors.forename: M
authors.initials: M
authors.lastname: Tijssen
authors.forename: W P H
authors.initials: WP
authors.lastname: de Boer
authors.forename: M
authors.initials: M
authors.lastname: van de Wiel
authors.forename: P R L A
authors.initials: PR
authors.lastname: van den Ijssel
authors.forename: P
authors.initials: P
authors.lastname: Jansen
authors.forename: P C
authors.initials: PC
authors.lastname: de Bruin
authors.forename: J H J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: G A
authors.initials: GA
authors.lastname: Meijer
authors.forename: C J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: J J
authors.initials: JJ
authors.lastname: Oudejans
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D053804:Granzymes / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D053804:Granzymes