TARGETING BCL‐2 IN ALK+ ALCL: AT THE CROSSROADS BETWEEN AUTOPHAGY AND APOPTOTIC CELL DEATH

Abstract

Introduction: Our research team has long been working on anaplastic large cell lymphoma (ALCL), a peripheral T-cell non-Hodgkin lymphoma representing up to 20% of childhood lymphomas. In more than 70% of the cases, the oncogenic tyrosine-kinase NPM-ALK is responsible for the tumorigenic process. Although chemotherapeutic treatments have proven to be efficient against the disease, relapses occur in approximately 30% of cases, thus revealing the need for new therapeutic weapons such as targeted therapies. Crizotinib is a specific inhibitor of the ALK activity, currently used in phase II clinical studies; however, resistance to this drug has already been reported. Our team has previously shown that Crizotinib treatment of ALK+ ALCL was responsible for promoting a cytoprotective type autophagy, which in turn may lead to the selection of Crizotinib-resistant cells. Interestingly, we recently observed that Crizotinib inhibition of ALK activity also induces expression of Bcl-2, which is often downregulated in ALK+ ALCL. Bcl-2 is a well-known oncogene and has been firmly established as both an anti-apoptotic factor and a key autophagy regulator. Methods: We carried out several in vivo and in vitro experiments to knock down the expression of BCL2 by miR-34a overexpression. Results: We show that blocking the Crizotinib-induced expression of Bcl-2 through overexpression of miR-34a (also used in clinical trials) enhances the anti-tumorigenic effect of Crizotinib. We demonstrate that Bcl-2 blockade not only increases Crizotinib induced apoptotic cell death but also results in an intensified autophagic flux, that switches from cytoprotective type to deleterious type, thus enhancing the anti-tumorigenic effect of Crizotinib. Conclusion: Taken together, our data suggest that through Bcl-2 targeting, the Crizotinib/miR-34a combination represents a promising therapeutic alternative to current treatments and provide new insights into cross-regulations between apoptosis and autophagy in lymphomas upon targeted-therapy. Keywords: ALK; anaplastic large cell lymphoma (ALCL); BCL2.