THE CRYPTIC INV(2)(P23Q35) DEFINES A NEW MOLECULAR-GENETIC SUBTYPE OFALK-POSITIVE ANAPLASTIC LARGE-CELL LYMPHOMA

Recently a distinctive entity characterized by expression of the anapl astic lymphoma kinase (ALK) protein [most frequently due to the t(2;5) (p23;q35)-associated NPM-ALK fusion] has emerged within the heterogeno us group of non-Hodgkin's lymphomas (NHL) classified as anaplastic lar ge-cell lymphoma (ALCL). Sporadic variant 2p23/ALK abnormalities ident ified in ALK-positive ALCL indicate that genes other than NPM may also be involved in the deregulation of ALK and lymphomagenesis. We report here three cases with an inv(2)(p23q35) detected by fluorescence in s itu hybridization (FISH) in young male patients with ALK-positive ALCL . In contrast to ALCL cases with the classical t(2;5)(p23;q35) that us ually show both cytoplasmic and nuclear or predominantly nuclear alone localization of the NPM-ALK chimeric product, in all three cases with an inv(2)(p23q35) the ALK protein accumulated in the cytoplasm only, supporting the previous assumption that the oncogenic potential of ALK may not be dependent on its nuclear localization. As the first step t o identify the ALK partner gene involved in the inv(2)(p23q35), we per formed extensive FISH studies and demonstrated that the 2q35 breakpoin t occurred within the 1,750-kb region contained within the 914E7 YAC. Moreover, a striking association of the inv(2)(p23q35) with a secondar y chromosomal change, viz, ider(2) (q10)inv(2)(p23q35), carrying two a dditional copies of the putative ALK-related fusion gene, was found in all three patients, suggesting that, in contrast to the standard t(2; 5)/NPM-ALK fusion, multiple copies of the putative 2q35-ALK chimeric g ene may be required for efficient tumor development. In summary, we de monstrate that the inv(2)(p23q35), a variant of the t(2; 5)(p23;q35), is a recurrent chromosomal abnormality in ALK-positive ALCL, the furth er characterization of which should provide new insight into the patho genesis of these lymphomas. (C) 1998 by The American Society of Hemato logy.