microRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma

• Published in: Blood Vol. 122; no. 12; pp. 2083 - 2092
• Main Authors: Liu, Cuiling, Iqbal, Javeed, Teruya-Feldstein, Julie, Shen, Yulei, Dabrowska, Magdalena Julia, Dybkaer, Karen, Lim, Megan S., Piva, Roberto, Barreca, Antonella, Pellegrino, Elisa, Spaccarotella, Elisa, Lachel, Cynthia M., Kucuk, Can, Jiang, Chun-Sun, Hu, Xiaozhou, Bhagavathi, Sharathkumar, Greiner, Timothy C., Weisenburger, Dennis D., Aoun, Patricia, Perkins, Sherrie L., McKeithan, Timothy W., Inghirami, Giorgio, Chan, Wing C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.09.2013; American Society of Hematology
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antigens, Surface - metabolism; Cell Line, Tumor; Child; Child, Preschool; Cluster Analysis; Female; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Order; Humans; Immunophenotyping; Lymphoid Neoplasia; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - metabolism; Lymphoma, Large-Cell, Anaplastic - pathology; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Neoplasm Staging; Organ Specificity - genetics; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; RNA Interference; T-Lymphocytes - metabolism; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-08-447375

Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[−]) ALCLs, 9 angioimmunoblastic T-cell lymphomas, 11 peripheral T-cell lymphomas not otherwise specified (PTCLNOS), and normal T cells, and demonstrated that ALCLs express many of the miRNAs that are highly expressed in normal T cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated distinct clustering of ALCL, PTCL-NOS, and the AITL subtype of PTCL. Cases of ALK(+) ALCL and ALK(–) ALCL were interspersed in unsupervised analysis, suggesting a close relationship at the molecular level. We identified an miRNA signature of 7 miRNAs (5 upregulated: miR-512-3p, miR-886-5p, miR-886-3p, miR-708, miR-135b; 2 downregulated: miR-146a, miR-155) significantly associated with ALK(+) ALCL cases. In addition, we derived an 11-miRNA signature (4 upregulated: miR-210, miR-197, miR-191, miR-512-3p; 7 downregulated: miR-451, miR-146a, miR-22, miR-455-3p, miR-455-5p, miR-143, miR-494) that differentiates ALK(–) ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs associated with ALK expression. Of these, the miR-17∼92 cluster and its paralogues were also highly expressed in ALK(+) ALCL and may represent important downstream effectors of the ALK oncogenic pathway. •Anaplastic large-cell lymphoma has a unique miRNA signature.•The miR-17∼92 is an important downstream effector of ALK oncogenic pathway.