Pathobiology of ALK+ anaplastic large-cell lymphoma

Abstract

Anaplastic large-cell lymphoma (ALCL) was initially recognized on the basis of morphologic features and the consistent expression of CD30. It then became evident that the majority of these tumors are derived from lymphoid cells of T or null immunophenotype. The subsequent finding that t(2;5)(p23;q35) occurs in 40% to 60% of ALCL patients established a distinct clinicopathologic entity. This chromosomal translocation induces the formation of the chimeric protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which possesses significant oncogenic potential resulting from the constitutive activation of the tyrosine kinase ALK. In addition to its specific pathophysiologic events, NPM-ALKexpressing lymphoma presents with consistent clinical manifestations. Only 13 years after the identification of NPM-ALK, tremendous progress has been made in our understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models. Several upstream modulators, cross-reacting oncogenes, and downstream effectors of NPM-ALK have been identified and characterized. Understanding these interacting oncogenic systems is expected to facilitate the design of new therapeutic strategies and agents. In this review, we briefly discuss ALCL and focus on NPM-ALK. IntroductionAnaplastic large-cell lymphoma (ALCL) is a relatively uncommon tumor. It was first recognized by Stein et al 1 in 1985, who reported the consistent expression of the Ki-1 antigen (later designated CD30) in tumors with frequent cohesive proliferation of large pleomorphic cells. Most of these tumors were labeled "histiocytic malignancies." 1 The Ki-1 monoclonal antibody was originally described by the same group and was used to identify a novel antigen in the Hodgkin lymphoma cell line L428. 2 Subsequent immunophenotyping and gene rearrangement studies showed that the vast majority of ALCL tumors are derived from lymphoid cells of T or null immunophenotype. 3 Histologically, several ALCL variants have been described. Of these variants, the common, lymphohistiocytic, and small-cell are the most frequently encountered. The "horseshoe" or "wreath" cell is considered the cytologic hallmark of this disease. 4 ALCL occurs as 2 distinct clinical entities, as a widespread systemic disease, or as a localized cutaneous disease. Systemic ALCL comprises 2% to 8% of non-Hodgkin lymphomas in adults and 10% to 15% of these lymphomas in children. 5 The frequency of ALCL increases to 30% to 40% of non-Hodgkin lymphomas in children when only cases with large-cell morphology are included. ALKThe recognition of t(2;5)(p23;q35) established the molecular definition of a subset of ALCL tumors that harbors this translocation. [6][7][8] In 1994, 2 independent groups cloned the genes involved in this translocation and illustrated the fusion of the nucleophosmin (NPM) gene on chromosome 5q35 to the previously unidentified gene anaplastic lymphoma kinase (ALK) gene on 2p23. 9,10 This chromosomal t...

Aberrant expression of IL-22 receptor 1 and autocrine IL-22 stimulation contribute to tumorigenicity in ALK+ anaplastic large cell lymphoma

“…The importance of IL-22 in contributing to STAT3 activation in these cells is further supported by our findings that blockade of IL-22 signaling using siRNA, IL-22BP or an IL-22-neutralizing antibody substantially decreased STAT3 activation. STAT3 activation in ALK þ ALCL is multifactorial; in addition to NPM-ALK, JAK3 and loss of SHP1 contributes to deregulate this signaling pathway, [32][33][34] it is not too surprising that the addition or blockade of IL-22 can only partially change the pSTAT3 levels in these cells. Although constitutive activation of STAT3 is crucial to the pathogenesis of ALK þ ALCL and NPM-ALK-mediated lymphomagenesis, 5,11 enhancement of STAT3 activation in these cells correlates well with the observed increased tumorigenicity induced by IL-22.…”

Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma

“…2 Anaplastic lymphoma kinase (ALK)-positive ALCL accounts for about 60% of ALCL and expresses an oncogenic ALK-fusion protein, resulting from a translocation involving most commonly the nucleophosmin (NPM) and ALK genes. 3,4 ALK À ALCL is morphologically similar to ALK þ ALCL, but lacks ALK expression. 5 Third, a primary cutaneous ALK À ALCL (cALCL) exists.…”

Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas

“…The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogene resulting from the t(2;5)(p23;q35) translocation is the causative agent of transformation of most anaplastic large cell lymphomas (ALCLs), as well as an increasing number of nonhematological disorders (Amin and Lai, 2007). Dimerization by the NPM domain leads to autophosphorylation of the tyrosine kinase, in which constitutive activation is oncogenic.…”