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Non-Hodgkin Lymphoma
miR-497 suppresses cycle progression through an axis involving CDK6 in ALK-positive cells
Ferrata Storti Foundation
Haematologica 2019 Volume 104(2):347-359
Coralie Hoareau-Aveilla,1,2,3* Cathy Quelen,1,2,3* Annabelle Congras,1,2,3#§
Nina Caillet,1,2,3#§ Delphine Labourdette,4 Christine Dozier,1,2,3
Pierre Brousset,1,2,3,5,6,7§ Laurence Lamant1,2,3,5,6,7§ and Fabienne Meggetto1,2,3,5,6,7§
1Inserm, UMR1037 CRCT, F-31000 Toulouse, France; 2Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France; 3CNRS, ERL5294 CRCT, F-31000 Toulouse, France; 4Laboratoire d’Ingénierie des Systèmes Biologiques et des Procédés, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France; 5Institut Carnot Lymphome-CALYM, F-31024 Toulouse, France; 6Laboratoire d’Excellence Toulouse Cancer-TOUCAN, F-31024 Toulouse, France and 7European Research Initiative on ALK- Related Malignancies, Cambridge, UK
*CH-A, CQ, AC, NC and FB all contributed equally to this work. §Member of the Equipe Labellisée LIGUE 2017.
ABSTRACT
Anaplastic large-cell lymphoma, a T-cell neoplasm, is primarily a pediatric disease. Seventy-five percent of pediatric anaplastic large-cell lymphoma cases harbor the chromosomal translocation t(2;5)(p23;q35) leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. NPM-ALK consists of an N-terminal nucle- ophosmin (NPM) domain fused to an anaplastic lymphoma kinase (ALK) cytoplasmic domain. Pediatric NPM-ALK+ anaplastic large-cell lym- phoma is often a disseminated disease and young patients are prone to chemoresistance or relapse shortly after chemotherapeutic treatment. Furthermore, there is no gold standard protocol for the treatment of relapses. To the best of our knowledge, this is the first study on the potential role of the microRNA, miR-497, in NPM-ALK+ anaplastic large- cell lymphoma tumorigenesis. Our results show that miR-497 expres- sion is repressed in NPM-ALK+ cell lines and patient samples through the hypermethylation of its promoter and the activity of NPM-ALK is responsible for this epigenetic repression. We demonstrate that overex- pression of miR-497 in human NPM-ALK+ anaplastic large-cell lym- phoma cells inhibits cellular growth and causes cell cycle arrest by tar- geting CDK6, E2F3 and CCNE1, the three regulators of the G1 phase of the cell cycle. Interestingly, we show that a scoring system based on CDK6, E2F3 and CCNE1 expression could help to identify relapsing pediatric patients. In addition, we demonstrate the sensitivity of NPM- ALK+ cells to CDK4/6 inhibition using for the first time a selective inhibitor, palbociclib. Together, our findings suggest that CDK6 could be a therapeutic target for the development of future treatments for NPM- ALK+ anaplastic large-cell lymphoma.
Introduction
Anaplastic large cell lymphoma (ALCL) is an aggressive form of T-cell non- Hodgkin lymphoma (NHL) with a constant membrane expression of the CD30 antigen, a cytokine receptor from the tumor necrosis factor receptor family. Four distinct entities of ALCL are currently recognized based on the 2016 revised World Health Organization (WHO) lymphoma classification: 1) anaplastic lymphoma kinase (ALK)-positive(+) ALCL; 2) ALK-negative (ALK–) ALCL; 3) primary cutaneous ALCL; and 4) breast implant-associated ALCL.1 ALCL accounts for approximately 10-15% of all NHL in children but is rare in adults (1-2% of adult NHL). Pediatricians have adopted ALCL99 chemotherapy including low cumulative doses of methotrexate, as standard therapy.2 Patients with pediatric ALCL have a favorable prognosis; however, systemic ALCL is
Correspondence:
fabienne.meggetto@inserm.fr
Received: April 9, 2018.
Accepted: September 21, 2018. Pre-published: September 27, 2018.
doi:10.3324/haematol.2018.195131
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