ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma

Abstract

We present 3 cases of large B-cell lymphoma (LBCL) with a granular cytoplasmic staining for anaplastic lymphoma kinase (ALK). All of the cases showed striking similarities in morphology and immunohistochemical profile characterized by a massive monomorphic proliferation of CD20 ؊ /CD138 ؉ plasmablast-like cells. In one of the cases, initially diagnosed as a null-type anaplastic large cell lymphoma (ALCL), the B-cell phenotype became evident only at recurrence. Fluorescent in situ hybridization (FISH) and molecular studies led to the detection of a CLTC-ALK rearrangement in all 3 cases, without any evidence of full-length ALK receptor expression. The associated t(2;17)(p23;q23) was demonstrated in the karyotype of 2 cases. Although a similar CLTC-ALK aberration was previously identified in ALK-positive T-/null cell ALCL and inflammatory myofibroblastic tumor, its association with ALK-positive LBCL seems to be specific and intriguing.

Diffuse large B-cell lymphomas with plasmablastic/plasmacytoid features are associated with TP53 deletions and poor clinical outcome

“…Recently, it has been shown that ALK activation in many of these B-cell lymphomas is due to a chromosomal translocation involving the CLTC gene on chromosome 17 instead of the overexpression of full-length ALK. 15,16 Even the 'classical' t(2;5)(p23;q35) with NPM as the fusion partner driving ALK overexpression has been reported to occur in DLBCL with plasmablastic morphology. 17 However, our lymphoma case lacks evidence of an altered ALK gene configuration, and it remains to be determined if the presence of ALK is a mere accident rather than an oncogenic phenomenon in these translocation-negative cases, in a similar manner as has been demonstrated for neuroblastomas expressing full-length ALK.…”

“…Recently, it has been demonstrated that most of these cases do not express full-length ALK, but instead show a translocation of ALK to the clathrin (CLTC) gene on chromosome 17. 15,16 Even the 'classical' translocation t(2;5)(p23;q35) involving the nucleophosmin (NPM) gene on chromosome 5q has been reported in two plasmablastic lymphomas. 17 Thus, the term 'plasmablastic' seems to encompass a wide and ever-growing spectrum of lymphomas with different clinical and biological features.…”

What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis?

“…13 In addition, CD30-negative diffuse large B-cell lymphomas expressing either NPM-ALK [14][15][16] or a variant clatherin-like polypeptide chain-ALK fusion protein have been reported. 17,18 Therefore, there is considerable heterogeneity in the human tumours caused by inappropriate expression of hyperactive ALK, and this is reflected also in the mouse tumour models that have been developed.…”

Novel clathrin activity: developments in health and disease

“…First, chromosomal translocation t(2;17)(p23;q23) fuses CHC17 with an intact trimerization domain (aa1-1634) to the C-terminus (aa1058-1620) of anaplastic lymphoma kinase (ALK) (40). The CHC-ALK fusion is often detected in non-Hodgkin's lymphomas and has been reported in anaplastic nul/T-cell lymphoma (41,42), large B-cell lymphoma (43)(44)(45)(46)(47)(48)(49)(50), and the rare inflammatory myofibroblastic tumor (51,52). To initiate ALKmediated lymphomagenesis, Stat3 must be activated (53).…”