Oncogenic Anaplastic Lymphoma Kinase Rearrangements in Lymphoma

Abstract

Lymphomas expressing anaplastic lymphoma kinase (ALK) represent two distinct lymphoma entities: ALK-positive T-/null-cell anaplastic large cell lymphoma (ALK + ALCL) and ALK-positive large B-cell lymphoma (ALK + LBCL). In both subtypes, the inappropriate expression of ALK is driven by 2p23/ALK-involving chromosomal translocations found to target several partner genes. These translocations lead to constitutively activated and oncogenic ALK fusions, of which nucleophosmin (NPM1)-ALK associated with t(2;5)(p23;q35) is the most common. Recently, various ALK fusions, including those previously described in lymphomas, have been identified in several types of nonhaematological malignancy. Identification of further types of ALK + tumours is clinically important because in future these patients may benefit from targeted therapy, already applied in neoplasms driven by, for example, the mutated ABL1, KIT and PDGFRA/B tyrosine kinases.In this article, we will focus mainly on oncogenic ALK rearrangements in lymphomas and their molecular consequences. KeywordsOncogene, anaplastic lymphoma kinase, anaplastic large cell lymphoma, large B-cell lymphoma The inappropriate expression of ALK in ALK + ALCL derives from chromosomal translocations targeting the 2p23/ALK locus. Occurring in 84% of ALK + ALCL, the most frequent, t(2;5)(p23;q35), results in the fusion of the amino-terminal end of NPM (currently designated as NPM1) with the intracytoplasmic portion of ALK.

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene

“…Even though the complete PTK domain is involved, the ALK fragment contains the final 513 amino acids, which is shorter in comparison to the fragment involved in most other ALK fusions, containing the final 563 amino acids. 42 Of note, both cases reported by Palacios et al 33 revealed breakpoints within intron 7 of EEF1G and intron 20 of ALK . As the fusions were identified by RNA-Seq, genetic mechanisms underlying these rearrangements are unknown.…”