Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like)

Anaplastic lymphoma kinase (ALK)-positive lymphomas are characterized by ex pression of a hybrid protein, comprising the cytoplasmic portion of the ALK tyrosine kinase fused to a partner protein. This hybrid kinase is often en coded by the nucleophosmin (NPM) NPM-ALK fusion gene resulting from the (2; 5)(p23; q35) chromosomal translocation, However, the ALK gene at 2p23 may a lso be involved in 2 variant translocations, namely t(1;2)(q25;p23) and t(2 ;3)(p23; q21), which create the TPM3-ALK and TFG-ALK fusion genes, respecti vely. We report here 2 lymphomas with an unusual finely granular cytoplasmi c ALK staining pattern, clearly different from the pattern observed in ALK- positive lymphomas carrying NPM-ALK or its variants. A cloned complementary DNA sequence from 1 of these 2 lymphomas contained the ALK gene fused to t he second clathrin heavy chain gene (also referred to as clathrin heavy pol ypeptide-like gene) (CLTCL), The distinctive granular cytoplasmic staining pattern for ALK was likely to be due to binding of the fusion protein to cl athrin-coated vesicles. The CLTCL gene is constitutively expressed in lymph oid cells and therefore presumably contributes an active promoter for the C LTCL-ALK gene. The fusion protein had a molecular weight (250 kd) that diff ers from all known ALK products, and it was autophosphorylated in an in vit ro kinase assay, confirming that it is constitutively active and hence capa ble of contributing to malignant transformation. These 2 cases, therefore, represent a hitherto undescribed mechanism of ALK activation in lymphoma an d further illustrate the diversity of fusion partners for the ALK gene. (C) 2000 by The American Society of Hematology.