(A) ALK receptor tyrosine kinase and the NPM–ALK fusion protein created by t(2;5). Fusion of the chromosome 5 gene encoding NPM to the chromosome 2 gene encoding ALK generates the chimeric tyrosine kinase, NPM–ALK. NPM contains an OD (residues 1–117) a putative MB (residues 104–115), two ADs (Asp/Glu-rich acidic domain; residues 120–132 and 161–188) that function as acceptor regions for nucleolar targeting signals and two NLS (residues 152–157 and 191–197). ALK contains a single MAM domain, a region of approximately 170 aa homologous to the extracellular portions of a number of functionally diverse proteins that may have an adhesive function (residues 480–635). The LBS for pleiotrophin and midkine (ALK residues 391–401) is indicated. Note that the entire intracytoplasmic portion of ALK, exclusive of the TM, is incorporated into the NPM–ALK and all other ALK chimeric proteins.
(B) Representative ALK fusion proteins, the chromosomalrearrangements that generate them, their occurrence in ALK-positivelymphomas and IMTs and their subcellular localizations. A partiallisting of the more common oncogenic ALK fusions is shown; a total of15 different ALK fusions have now been described (those not shown are ALO17–ALK, CARS–ALK, MYH9–ALK, SEC31L1– ALK and TFGXL–ALK). The exact frequency of the various ALK fusions expressed in IMT has not yet been determined. To date, six ALK fusions (CARS–ALK, CLTC–ALK, RANBP2–ALK, SEC31L1–ALK, TPM3–ALK and TPM4–ALK) have been identified in IMT. The TPM3–ALK, TPM4–ALK and CLTC–ALK fusions have been detected in both classical null or T-cell anaplastic large-cell lymphomas and IMT, whereas CARS-ALK, RANBP2–ALK and SEC31L1–ALK occur in IMT but have not yet been described in anaplastic large-cell lymphoma. CLTC–ALK and, to a lesser extent, NPM–ALK, also occur in rare B-cell plasmablastic/immunoblastic non-Hodgkin’s lymphomas. Two independent reports have also recently described the occurrence of the TPM4–ALK fusion in squamous cell carcinomas of the esophagus [177,178], and several studies have identified the presence of the novel ALK fusion, EML4–ALK, in a subset of non-small-cell lung cancers [180-187]. aa: Amino acid; AD: Acidic amino acid domain; ALK: Anaplastic lymphoma kinase; ATIC: 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase; C: Cytosolic; CLTC: Clathrin heavy chain; CM: Cell membrane; EML: Echinoderm microtubule-associated protein-like; LBS: Ligand-binding site; IMT: Inflammatory myofibroblastic tumor; MAM: Meprin/A5/protein tyrosine phosphatase Mu; MB: Metal-binding domain; MSN: Moesin; N: Nuclear; NLS: Nuclear localization signal; NPM: Nucleophosmin; NM: Nuclear membrane; OD: Oligomerization domain; RanBP2: Ran-binding protein 2; TFG: TRK-fused gene; TK: Tyrosine kinase catalytic domain; TM: Transmembrane domain; TPM3: Non-muscle tropomyosi.