Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma.

A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo.

Crescenzo R ，Abate F ，Lasorsa E ，Tabbo' F ，Gaudiano M ，Chiesa N ，Di Giacomo F ，Spaccarotella E ，Barbarossa L ，Ercole E ，Todaro M ，Boi M ，Acquaviva A ，Ficarra E ，Novero D ，Rinaldi A ，Tousseyn T ，Rosenwald A ，Kenner L ，Cerroni L ，Tzankov A ，Ponzoni M ，Paulli M ，Weisenburger D ，Chan WC ，Iqbal J ，Piris MA ，Zamo' A ，Ciardullo C ，Rossi D ，Gaidano G ，Pileri S ，Tiacci E ，Falini B ，Shultz LD ，Mevellec L ，Vialard JE ，Piva R ，Bertoni F ，Rabadan R ，Inghirami G ，European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium “Genetics-Driven Targeted Management of Lymphoid Malignancies” ... -  《-》

Cytokine receptor signaling is required for the survival of ALK- anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations.

Chen J ，Zhang Y ，Petrus MN ，Xiao W ，Nicolae A ，Raffeld M ，Pittaluga S ，Bamford RN ，Nakagawa M ，Ouyang ST ，Epstein AL ，Kadin ME ，Del Mistro A ，Woessner R ，Jaffe ES ，Waldmann TA ... -  《-》

A novel model of alternative NF-κB pathway activation in anaplastic large cell lymphoma.

Wang H ，Wei W ，Zhang JP ，Song Z ，Li Y ，Xiao W ，Liu Y ，Zeng MS ，Petrus MN ，Thomas CJ ，Kadin ME ，Nakagawa M ，Waldmann TA ，Yang Y ... -  《-》

Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma.

Prutsch N ，Gurnhofer E ，Suske T ，Liang HC ，Schlederer M ，Roos S ，Wu LC ，Simonitsch-Klupp I ，Alvarez-Hernandez A ，Kornauth C ，Leone DA ，Svinka J ，Eferl R ，Limberger T ，Aufinger A ，Shirsath N ，Wolf P ，Hielscher T ，Sternberg C ，Aberger F ，Schmoellerl J ，Stoiber D ，Strobl B ，Jäger U ，Staber PB ，Grebien F ，Moriggl R ，Müller M ，Inghirami GG ，Sanda T ，Look AT ，Turner SD ，Kenner L ，Merkel O ... -  《-》

JAK/STAT3 Signaling Activation Related to Distinct Clinicopathologic Features in Systemic ALK - Anaplastic Large Cell Lymphomas : New Insights into Their Heterogeneity.

Systemic anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a group of heterogenous CD30 + T-cell non-Hodgkin lymphomas. Previous studies have highlighted the importance of JAK/STAT3 signaling activation in the molecular pathogenesis of ALK - ALCLs. In the present study, we aimed to establish a potential relationship between JAK/STAT3 signaling activation and clinicopathologic features in ALK - ALCLs, and further recognize the heterogenous nature of these neoplasms. Immunohistochemistry staining of the phosphorylated-STAT3 (p-STAT3) and dual-specificity protein phosphatase 22 ( DUSP22 ) gene rearrangement analysis were performed. Forty-five cases of ALK - ALCL were divided into 3 groups, including 9 DUSP22 -rearranged ALCLs, 21 p-STAT3 + double-negative (DN) ALCLs (both ALK and DUSP22 rearrangement negative), and 15 p-STAT3 - DN-ALCLs. Morphologically, p-STAT3 + DN-ALCLs exhibited sheet-like neoplastic cells and sometimes showed large pleomorphic cells scattered in a lymphocyte-rich background more frequently than those in other ALK - ALCLs subtypes. Phenotypically, the p-STAT3 + DN-ALCLs frequently expressed cytotoxic molecules, epithelial membrane antigen, and programmed death-ligand 1, whereas CD3 and CD5 expression was not observed. Clinically, patients with p-STAT3 + DN-ALCLs had a better prognosis than those with p-STAT3 - DN-ALCLs. These observations suggest that p-STAT3 + DN-ALCLs represent a distinct subtype of ALK - ALCLs. Identifying ALK - ALCL subtypes by using p-STAT3 staining and DUSP22 rearrangement is a promising approach that may contribute to risk stratification and better treatment decisions in the future clinical practice.

Wang JC ，Zhong LH ，Lin WQ ，Zhang WF ，Xi YF ，Liu YP ，Zhu Q ，Liu W ，Zhu WF ，Chen YP ，Chen G ... -  《-》