title: Beyond NPM-anaplastic lymphoma kinase driven lymphomagenesis: alternative drivers in anaplastic large cell lymphoma.
abstract: OBJECTIVE
  Anaplastic large cell lymphomas (ALCLs) are rare entities whose somatic genetic lesions have been identified only in a subset of patients. Thus, an integrated and massive discovery programme is required to define their tumourigenic alterations and to design more successful tailored therapies.
  
  
  RESULTS
  The discovery of anaplastic lymphoma kinase (ALK) fusions has provided the basis for the characterization of distinct subsets among ALCL patients. Although the oncogenic addiction of ALK signalling is proven, the tumorigenic contribution of coactivating lesions is still missing. As ALK- and ALK+ share common signatures, it is plausible that analogous mechanisms of transformation may be operating in both subsets, as confirmed by the dysregulated activation of c-MYC, RAS and NFκB, and the loss of Blimp-1 and p53/p63 axis. Nonetheless, recurrent genetic alterations for ALK- ALCL or refractory leukaemic ALK+ ALCL are lacking. Moreover, although conventional chemotherapies (anthracycline-based) are most successful, that is in ALK+ ALCL patients, the implementation of ALK inhibitors or of anti-CD30 based treatments provides innovative solutions, particularly in paediatric ALK+ ALCL and in chemorefractory/relapsed patients.
  
  
  CONCLUSIONS
  The complete portrayal of the landscape of genetic alterations in ALCL will dictate the development of innovative chemotherapeutic and targeted therapies that will fit most with the molecular and clinical profiling of individual patients.
authors.affiliation: Department of Molecular Biotechnology and Health Science, Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tabbò
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases