A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.

Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies

Anaplastic large-cell lymphoma.

The concept of anaplastic large-cell lymphoma (ALCL) has changed over the years because of a stream of new information and novel understanding regarding the cell of origin, biology, genetics, and clinical features of these neoplasms. This new information has led to the current classification proposed by the expert reviewers of the World Health Organization. The objective of this review is to present the most updated information on the cytologic and histologic features of these entities, with a special reference to diagnostic algorithms. A detailed description of the genetic aberrations and the pathogenetic mechanisms leading to transformation is presented. The clinical features of ALCL and novel tailored strategies are briefly illustrated

Anaplastic lymphoma kinase in human cancer.

The receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. Their pivotal function has been firmly established in the pathogenesis of many cancers as well. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)-ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. In this review, we describe the expression of the ALK-RTK, its related fusion proteins, and their molecular mechanisms of activation. Novel tailored strategies are briefly illustrated for the treatment of ALK-positive neoplasms

Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma

JAK/STAT3 signaling pathway is often deregulated in hematopoietic disorders including peripheral T-cell lymphoma. We describe two novel mechanisms leading to the constitutive activation of STAT3 in ALK- ALCL. Oncogenic JAK1 or STAT3 mutations are associated to hyperactive pSTAT3 that regulated canonical STAT3 and ATF3 genes. Moreover, synergizing JAK1 and STAT3 mutants sustain the neoplastic growth, which can be efficiently controlled in vitro and in an ALCL patient derived tumorgraft model by JAK1/2 inhibitors. We have discovered that novel chimera, displaying concomitant transcriptional and kinase activities, are power oncogenes capable to sustain via STAT3 the ALCL phenotype and can be uniquely neutralized by a novel ROS1 inhibitor. The pharmacological inhibition of JAK/STAT3 represents a novel strategy for the treatment of molecular stratified ALCL