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Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1428-1439
Non-Hodgkin Lymphoma
Blockade of crizotinib-induced BCL2 elevation in ALK-positive anaplastic large cell lymphoma triggers autophagy associated with cell death
Avedis Torossian,1,2,3 Nicolas Broin,1,2,3 Julie Frentzel,1,2,3 Camille Daugrois,1,2,3,4 Sarah Gandarillas,5 Talal Al Saati,6 Laurence Lamant,1,2,3,4,7,8
Pierre Brousset,1,2,3,4,7,8 Sylvie Giuriato,1,2,3,8,9 and Estelle Espinos1,2,3,4,8
1Inserm, UMR1037 CRCT, F-31000 Toulouse, France; 2Université Toulouse III-Paul
3
Sabatier, UMR1037 CRCT, F-31000 Toulouse, France; CNRS, ERL5294 UMR1037 CRCT,
F-31000, Toulouse, France; 4Laboratoire d'Excellence Toulouse-Cancer-TOUCAN, F-31024 Toulouse, France; 5Inserm/UPS, US006/CREFRE, F-31000 Toulouse, France; 6Inserm/UPS, US006/CREFRE, Service d'Histopathologie, F-31000 Toulouse, France; 7Département de Pathologie, IUCT, F-31000 Toulouse, France; 8European Research Initiative on ALK-related Malignancies (ERIA), Cambridge, UK and 9Transautophagy: European network for multidisciplinary research and translation of autophagy knowledge, COST Action CA15138, Brussel, Belgium
ABSTRACT
Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphomas are tumors that carry translocations involving the ALK gene at the 2p23 locus, leading to the expression of ALK tyro- sine kinase fusion oncoproteins. Amongst hematologic malignancies, these lymphomas are particular in that they express very low levels of B- cell lymphoma 2 (BCL2), a recognized inhibitor of apoptosis and autophagy, two processes that share complex interconnections. We have previously shown that treatment of ALK-positive anaplastic large cell lymphoma cells with the ALK tyrosine kinase inhibitor crizotinib induces autophagy as a pro-survival response. Here, we observed that crizotinib- mediated inactivation of ALK caused an increase in BCL2 levels that restrained the cytotoxic effects of the drug. BCL2 downregulation in com- bination with crizotinib treatment potentiated loss of cell viability through both an increase in autophagic flux and cell death, including apoptosis. More importantly, our data revealed that the blockade of autophagic flux completely reversed impaired cell viability, which demonstrates that excessive autophagy is associated with cell death. We propose that the downregulation of BCL2 protein, which plays a central role in the autophagic and apoptotic machinery, combined with crizo- tinib treatment may represent a promising therapeutic alternative to cur- rent ALK-positive anaplastic large cell lymphoma treatments.
Introduction
Anaplastic large cell lymphoma (ALCL) is an aggressive subtype of peripheral T- cell non-Hodgkin lymphoma that accounts for 10-15% of childhood lymphomas.1 Two systemic forms of ALCL are currently recognized based on the 2016 revised World Health Organization (WHO) lymphoma classification,2 according to the presence or absence of chromosomal translocations involving the anaplastic lym- phoma kinase (ALK) gene at the 2p23 locus. Almost 90% of ALK-positive ALCL in children carry a characteristic t(2;5) (p23;q35) chromosomal translocation, leading to the intracellular expression of the oncogenic fusion protein nucleophosmin (NPM)-ALK.3 ALK fusion proteins are constitutively active tyrosine kinases that lead to the activation of several downstream pathways, such as MEK/ERK, STATs and PI3K/AKT/mTOR, which result in abnormal proliferation and cell survival.4,5
Current standard therapies for ALCL in children and adolescents, most common-
Correspondence:
ESTELLE ESPINOS
estelle.espinos@inserm.fr/
SYLVIE GIURIATO
sylvie.giuriato@inserm.fr
Received: October 11, 2017. Accepted: January 22, 2019. Pre-published: January 24, 2019.
doi:10.3324/haematol.2017.181966
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