Summary 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 155 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.

Until recently the left atrium had been subordinate to the left ventricle, but cardiologists now recognize that left atrial (LA) function is indispensable to normal circulatory performance. Transthoracic two-dimensional (2D) and Doppler echocardiography can elucidate parameters of LA function non-invasively. Yet, with the advent of 2D speckle-tracking echocardiography, we are able to detect early LA dysfunction even before structural changes occur. This is pivotal in some common disease states, such as atrial fibrillation, hypertension, and heart failure, in which LA deformation parameters can influence clinical management. However, a unique standardized technique to investigate LA deformation needs to be validated.

Following publication of the manuscript, the authors identified an inadvertent error in the summary. The analysis exploring the presence of activating mutations in JAK1 and/or STAT3 was conducted in a total of 155 ALCLs, of which 88 were systemic ALK À ALCLs. The ''155'' in the sentence ''We identified activating mutations of JAK1 and/or STAT3 genes in $20% of 155 ALK À ALCLs and demonstrated that 38% of systemic ALK À ALCLs displayed double lesions'' therefore should be ''88'' instead. The correct sentence should read as follows: ''We identified activating mutations of JAK1 and/or STAT3 genes in $20% of 88 ALK À ALCLs and demonstrated that 38% of systemic ALK À ALCLs displayed double lesions.'' The error has been corrected in the online version of the article.

Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin lymphoma found in children and young adults with poor survival rates. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK triggered lymphoma growth are still not entirely clear. Here we show that the AP-1 proteins cJun and JunB promote lymphoma development and tumor dissemination in a murine NPM-ALK lymphomagenesis model via transcriptional regulation of PDGFRB. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Remarkably, inhibition of PDGFRs in a late stage patient with refractory NPM-ALK-positive ALCL resulted in complete and sustained remission within 10 days of treatment. Our data identify PDGFRB as novel cJun/JunB target that could be utilized for a highly effective therapy to cure ALCL. 3ALCLs are T-cell lymphomas 1,2 that comprise 10-20% of all Non-Hodgkin's lymphoma cases in children and 3% in adults 3 . About half of ALCL cases are positive for NPM-ALK fusion proteins caused by t(2;5)(p23;q35) translocation 4 . ALK translocations or point mutations have also been described in DLBCLs (diffuse large B-cell lymphomas) and in several nonlymphoid neoplasms [5][6][7][8] . Inhibition of ALK fusion proteins by specific compounds such as crizotinib showed promising clinical responses in ALCL and NSCLC (non-small cell lung cancer) 9,10 . However, ALK mutations conferring resistance to crizotinib have also been reported 11 .Recent studies have linked NPM-ALK expression to induction of AP-1 transcription factors JunB and cJun 12,13 . To investigate their role in NPM-ALK-driven T-cell lymphomas, we conditionally deleted cJun and/or JunB in T-cells of transgenic mice carrying the human NPM-ALK fusion-tyrosine-kinase under the control of the murine CD4-promotor 14 (CD4-NPM-ALK) (Fig. 1a). Gene deletion was confirmed by DNA genotyping (data not shown), real-time PCR, Western blotting and immunohistochemistry (IHC) (Suppl. (Fig.1b), however, inactivation of both, cJun and JunB, in CD4-NPM-ALK-CD4 ΔΔJun mice resulted in significantly prolonged survival (Fig. 1b). CD4-NPM-ALK-CD4 ΔΔJun lymphomas showed markedly reduced proliferation and significantly increased apoptosis when compared to CD4-NPM-ALK lymphomas ( Fig. 1c; Suppl. Fig. S2a,b). Consistently, (Fig. 2d) suggesting a transcriptional regulation of PDGFRB by Jun proteins. Consistently, AP-1 consensus sequences were identified within the murine PDGFRB promoter and first intron that were conserved among other species (Suppl. Fig. S3b,c) 15,16 . Moreover, analysis of ENCODE transcription factor binding tracks revealed binding of cJun and JunB to the PDGFRB intronic AP-1 site in the human K562 leukemia cell line (Suppl. Fig. S3d) 15,17 . CD4-NPM-ALK-CD4EMSA analysis of nuclear extracts from NPM-ALK lymphomas demonstrated AP-1 DNA ...

Key Points• The commonest lesions in anaplastic large cell lymphomas are losses at 17p13 and at 6q21, concomitant in up to onequarter of the cases. • PRDM1 (BLIMP1) gene (6q21) is inactivated by multiple mechanisms and acts as a tumor suppressor gene in anaplastic large B-cell lymphoma.Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2% to 5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the anaplastic lymphoma kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK 1 and ALK 2 ALCL subtypes, we performed a genome-wide DNA profiling using high-density, single nucleotide polymorphism arrays on a series of 64 cases and 7 cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes, respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK 2 ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an antiapoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK 2 ALCL, and in 29% of all ALCL cases with a clinical implication. (Blood. 2013;122(15):2683-2693

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Accessory mitral valve tissue (AMVT) is a rare congenital cardiac anomaly sometimes responsible for left ventricular outflow tract (LVOT) obstruction. It is diagnosed during both neonate-childhood and adult periods in patients usually symptomatic for dyspnoea, chest pain, palpitations, fatigue, or syncope. Nevertheless, AMVT is often an incidental finding. AMVT is most often associated with other cardiac and vascular congenital malformations, such as septal defects and transposition of the great arteries. Surgery is indicated only in cases of significant LVOT obstruction and in patients undergoing correction of other cardiac malformations or exploration of an intracardiac mass. Two-dimensional echocardiography, both transthoracic and transoesophageal, is considered the main imaging modality for AMVT diagnosis and patient follow-up. The recent introduction of three-dimensional echocardiography allows a more realistic characterization of this entity. We present three clinical cases in which AMVT was incidentally diagnosed during standard echocardiography and an updated review of the literature highlighting the usefulness of echocardiography for AMVT morphological and functional characterization as well as the most relevant clinical implications due to its discovery.

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