title: The Wnt signaling pathway and mitotic regulators in the initiation and evolution of mantle cell lymphoma: Gene expression analysis.
abstract: For an accurate understanding of mantle cell lymphoma (MCL), molecular behavior could be staged into two major events: lymphomagenesis with the t(11;14) translocation (initiation), and evolution into a more aggressive form (transformation). Unfortunately, it is still unknown which genes contribute to each event. In this study, we performed cDNA microarray experiments designed based on the concept that morphologically heterogeneous MCL samples would provide insights into the role of aberrant gene expression for both events. A total of 15 MCLs were collected from the files, which include a total of 237 MCL patients confirmed by histology as CCND1-positive. We posited four stepwise morphological grades for MCL: MCL in situ, MCL with classical form (cMCL), MCL with aggressive form (aMCL), and MCL with intermediate morphology between classical and aggressive forms at the same site (iMCL). To identify genes involved in initiation, we compared the tumor cells of MCL in situ (n=4) with normal mantle zone B lymphocytes (n=4), which were selected by laser microdissection (LMD). To identify genes contributing to transformation, we selected the overlapping genes differentially expressed between both cMCL (n=4) vs. aMCL (n=5) and classical vs. aggressive areas in iMCL (n=2) obtained by LMD. A significant number of genes (n=23, p=0.016) belonging to the Wnt signaling pathway were differentially expressed in initiation. This specific activation was confirmed by immuno-histochemistry, as MCL in situ had nuclear localization of phosphorylated-β-catenin with high levels of cytoplasmic Wnt3 staining. For transformation, identified 60 overlapping genes included a number of members of the p53 interaction network (CDC2, BIRC5 and FOXM1), which is known to mediate cell cycle progression during the G2/M transition. Thus, we observe that the Wnt signaling pathway may play an important role in initial lymphomagenesis in addition to t(11;14) translocations, and that specific mitotic regulators facilitate transformation into more aggressive forms.
authors.affiliation: Department of Pathology, School of Medicine, Kurume University, Kurume, Fukuoka, Japan. kimura_yoshizou@kurume-u.ac.jp
authors.forename: Yoshizo
authors.initials: Y
authors.lastname: Kimura
authors.forename: Fumiko
authors.initials: F
authors.lastname: Arakawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Kiyasu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyoshi
authors.forename: Maki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Ayako
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Niino
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sugita
authors.forename: Takashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Atushi
authors.initials: A
authors.lastname: Doi
authors.forename: Kaori
authors.initials: K
authors.lastname: Yasuda
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tashiro
authors.forename: Satoru
authors.initials: S
authors.lastname: Kuhara
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D016203:CDC2 Protein Kinase; D019926:Cyclin B / Q000235:genetics; D018844:Cyclin-Dependent Kinases; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*; D060508:Wnt3 Protein / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D019926:Cyclin B; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C555507:WNT3 protein, human; D060508:Wnt3 Protein; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases