title: Differential expression of cyclin D3 in ALK+ and ALK- anaplastic large cell lymphoma.
abstract: As defined in the World Health Organization classification, anaplastic large cell lymphoma (ALCL) is a distinct type of non-Hodgkin lymphoma of T/null cell lineage, a subset of which is associated with translocations involving 2p23 resulting in expression of anaplastic lymphoma kinase (ALK). The most common translocation, the t(2;5)(p23;q35), results in expression of nucleophosmin (NPM)-ALK. NPM-ALK has been shown to activate signal transducer and activator of transcription (STAT) 3, a transcriptional regulator of cyclin D3. In this study, we assessed cyclin D3 expression in 2 ALK+ ALCL cell lines (Karpas 299 and SU-DHL1) and 1 ALK- ALCL cell line (Mac2A) by Western blot analysis. We also assessed cyclin D3 expression in 52 ALCL tumors (32 ALK+, 20 ALK-) by immunohistochemistry using tissue microarrays. These results were compared with phosphorylated (activated) STAT3 (pSTAT3) expression. Both ALK+ ALCL cell lines, but not the ALK- ALCL cell line, expressed cyclin D3 and pSTAT3. Cyclin D3 was expressed in 25 (78%) of 32 ALK+ ALCL tumors and in 4 (20%) of 20 ALK- ALCL tumors (P < .001, Fisher exact test ). In ALK+ ALCL tumors, the mean percentage of cyclin D3-positive tumor cells was 40.6% compared with 5.1% in ALK- ALCL tumors (P < .001, Mann-Whitney U test). The percentages of cyclin D3-positive and pSTAT3-positive tumor cells were positively correlated (Spearman R = 0.35, P = .036). We conclude that cyclin D3 is differentially expressed in ALK+ and ALK- ALCL and that high expression levels of cyclin D3 in ALK+ ALCL may be attributable to STAT3 activation.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Rory R
authors.initials: RR
authors.lastname: Dalton
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
authors.forename: Coralyn
authors.initials: C
authors.lastname: Atwell
authors.forename: Sarah
authors.initials: S
authors.lastname: Wang
authors.forename: Mauricio P
authors.initials: MP
authors.lastname: Oyarzo
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D015153:Blotting, Western; D002452:Cell Count; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D040081:Protein Array Analysis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor; D015996:Survival Rate; D015534:Trans-Activators / Q000378:metabolism
chemical_list: C534696:CCND3 protein, human; D056743:Cyclin D3; D016213:Cyclins; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases