Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma

• Published in: Blood Vol. 114; no. 14; pp. 2945 - 2951
• Main Authors: Navarro, Alfons, Diaz, Tania, Martinez, Antonio, Gaya, Anna, Pons, Aina, Gel, Bernat, Codony, Carles, Ferrer, Gerardo, Martinez, Carmen, Montserrat, Emili, Monzo, Mariano
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-10-2009; Americain Society of Hematology
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Apoptosis; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Female; Hematologic and hematopoietic diseases; Hodgkin Disease - genetics; Hodgkin Disease - metabolism; Hodgkin Disease - pathology; Humans; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Luciferases; Male; Medical sciences; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Survival Rate; Transfection; Young Adult; Human; Prognosis; Enzyme; JAK2 protein tyrosine kinase; Transferases; Micro RNA; Hodgkin disease; Malignant hemopathy; Gene expression; Lymphoma; Gene silencing; Regulation(control); Lymphoproliferative syndrome; Genetics; Protein-tyrosine kinase; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-02-204842

The behavior of classic Hodgkin lymphoma (cHL) is determined by both the intrinsic features of the tumor cells and the characteristics of the microenvironment, making the analysis of entire lymph nodes an effective approach to understanding the disease. We examined the influence of our previously reported 25-microRNA signature for cHL on clinical outcome in 89 homogeneously treated cHL patients with a median follow-up of 80 months. Patients with low miR-135a expression had a higher probability of relapse (P = .04) and a shorter disease-free survival (P = .02). Functional analysis of cHL cell lines showed that mature miR-135a levels increased after pre–miR-135a transfection, causing apoptosis and decreased cell growth. Target analysis showed a direct regulation by miR-135a of JAK2, a cytoplasmic tyrosine kinase involved in a specific subset of cytokine receptor signaling pathways. miR-135a–mediated JAK2 down-regulation led to decreased mRNA and protein levels of the antiapoptotic gene Bcl-xL, suggesting a role for Bcl-xL in miR-135a/JAK2–mediated apoptosis. Our findings confirm the critical role of miR-135a in the survival of cHL cells and in the prognosis of cHL patients, indicating that novel treatment approaches targeting miR-135a may potentially benefit these patients.