Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumor

Abstract

ALK-positive anaplastic large-cell lymphoma (ALCL) has been recognized as a distinct type of lymphoma in the heterogeneous group of T/Null-ALCL. While most of the ALK-positive ALCL (ALKomas) are characterized by the presence of the NPM-ALK fusion protein, the product of the t(2;5)(p23;q35), 10-20% of ALKomas contain variant ALK fusions, including ATIC-ALK, TFG-ALK, CLTC-ALK (previously designated CLTCL-ALK), TMP3-ALK, and MSN-ALK. TMP3-ALK and TMP4-ALK fusions also have been detected in inflammatory myofibroblastic tumors (IMTs), making clear that aberrations of the ALK gene are not associated exclusively with the pathogenesis of ALK-positive ALCL. Here we report results of molecular studies on two lymphoma cases and one IMT case with variant rearrangements of ALK. Our study led to the detection of the CLTC-ALK fusion in an ALCL case and to the identification of two novel fusion partners of ALK: ALO17 (KIAA1618), a gene with unknown function, which was fused to ALK in an ALCL case with a t(2;17)(p23;q25), and CARS, encoding the cysteinyl-tRNA synthetase, which was fused to ALK in an IMT case with a t(2;11;2)(p23;p15;q31). These results confirm the recurrent involvement of ALK in IMT and further demonstrate the diversity of ALK fusion partners, with the ability to homodimerize as a common characteristic.

Diffuse large B-cell lymphoma: a heterogeneous group of non-Hodgkin lymphomas comprising several distinct clinicopathological entities

“…Aberrant ALK expression has been described in anaplastic large-cell lymphomas and inflammatory myofibroblastic tumors and results from genomic rearrangements of the ALK gene with various partner genes. [48][49][50][51] ALK expression in DLBCL is not the result of full-length ALK expression as originally reported 52 but is due, in most of the cases, to a recurrent translocation t(2;17)(p23;q23) resulting in the CLTC-ALK fusion protein. 43,44 In a few cases ALK expression in these tumors can also result from the t(2;5)(p23;q35) translocation leading to the NPM (nucleophosmin)-ALK fusion protein.…”

ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases

“…5 However, a number of recent studies have identified a growing list of alternative translocation partners (X-ALK) that appear also to activate ALK. [16][17][18][19][20][21][22] All of these are characterized by changes in the subcellular localization of ALK, being located either within the nucleus, nucleolus, and cytoplasm, restricted to the cytoplasm, or in the cytoplasmic membrane. Recognition of these variant translocations suggests that nuclear and nucleolar localization of ALK, as seen in cases with the t(2;5), is not critical to pathogenesis.…”

Utility of ALK-1 protein expression and ALK rearrangements in distinguishing inflammatory myofibroblastic tumor from malignant spindle cell lesions of the urinary bladder

“…4,5,7,9,[20][21][22][23][24][25][29][30][31][32] Cytogenetic and molecular analyses have demonstrated a number of ALK fusion gene partners, including RANBP2-ALK, TPM3-ALK, TPM4-ALK, CLTCALK, CARS-ALK and SEC31L1-ALK. 5,9,21,25,29,31 In the present study, ALK rearrangements were identified in 14 of 21 cases of inflammatory myofibroblastic tumor of the urinary bladder.…”