Abstract
ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.
Highlights
Expression of anaplastic lymphoma kinase (ALK) fusion proteins resulting from chromosomal translocations involving chromosome band 2p23 is a hallmark of anaplastic large cell lymphomas (ALCL) [1]
From the published case reports based on approximately 50 patients, these lymphomas seem to be associated with a poor outcome in children and adults compared to both ALK-positive ALCL and ALK-negative Diffuse large B cell lymphomas (DLBCL) when treated with current chemotherapy regimens [8,9]
We report the characterization of the first CTLC-ALK positive DLBCL cell line (LM1), the establishment of a pre-clinical model to study the role of CLTCALK activity in DLBCL lymphomagenesis, and demonstrate that these lymphomas display activation of ALK signalling pathways and are potently suppressed in vitro and in vivo by a selective ALK inhibitor
Summary
Expression of anaplastic lymphoma kinase (ALK) fusion proteins resulting from chromosomal translocations involving chromosome band 2p23 is a hallmark of anaplastic large cell lymphomas (ALCL) [1]. Diffuse large B cell lymphomas (DLBCL) harbouring ALK fusion proteins were first described in 1997 [4] With few exceptions these ALK-translocated DLBCLs display a fine granular cytoplasmic ALK-staining characteristic for the fusion of clathrin (CLTC) with ALK caused by the reciprocal translocation t(2;17)(p23;q23) [5,6,7]. These DLBCLs are further characterized by the expression of immunoglobulin light chain kappa or lambda, plasma cell associated antigens CD38 and CD138, and epithelial membrane antigen (EMA), but lack expression of CD30 antigen and many other B- and T-cell markers [4,6,7]. From the published case reports based on approximately 50 patients, these lymphomas seem to be associated with a poor outcome in children and adults compared to both ALK-positive ALCL and ALK-negative DLBCL when treated with current chemotherapy regimens [8,9]
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