The transition from juvenile to adult life is accompanied by programmed remodeling in many tissues and organs, which is key for organisms to adapt to the demand of the environment. Here we report a novel regulated alternative splicing program that is crucial for postnatnal heart remodeling in the mouse. We identify the essential splicing factor ASF/SF2 as a key component of the program, regulating a restricted set of tissue-specific alternative splicing events during heart remodeling. Cardiomyocytes deficient in ASF/SF2 display an unexpected hypercontraction phenotype due to a defect in postnatal splicing switch of the Ca(2+)/calmodulin-dependent kinase IIdelta (CaMKIIdelta) transcript. This failure results in mistargeting of the kinase to sarcolemmal membranes, causing severe excitation-contraction coupling defects. Our results validate ASF/SF2 as a fundamental splicing regulator in the reprogramming pathway and reveal the central contribution of ASF/SF2-regulated CaMKIIdelta alternative splicing to functional remodeling in developing heart.

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Key Points Ten cases of an indolent T-cell lymphoproliferative disease of the gastrointestinal tract are reported. It is important to recognize this condition because it can be mistaken for aggressive T-cell lymphoma, which may lead to unnecessary therapy.

© F e r r a t a S t o r t i F o u n d a t i o nBCL2 translocations are more frequently found in the GCB subtype, whereas 18q21 locus amplification is more common in the ABC subtype of DLBCL. 3,8,10 The prognostic significance of BCL2 amplification or translocations in de novo DLBCL in the era of CHOP therapy alone, without rituximab, was controversial. [11][12][13][14][15][16][17][18][19][20] Some data on the prognostic significance of BCL2 aberrations in patients treated with R-CHOP have recently become available, with two studies reporting no influence of BCL2 gene rearrangements on the survival of DLBCL patients. 21,22 On the other hand, the concomitant presence of t(14;18) or variants and MYC rearrangements, referred to as double hit lymphomas, has consistently been associated with adverse outcome in DLBCL patients treated with R-CHOP. [23][24][25] Bcl-2 protein expression seems only partially related to BCL2 gene abnormalities as analyzed by fluorescence in situ hybridization (FISH), as Bcl-2 is expressed in a greater number of DLBCL cases than in those tumors carrying t(14;18)(q32;q21). [10][11][12] Indeed, in the absence of BCL2 translocations, amplification of 18q21 and/or activation of the nuclear factor κB (NF-κB) pathway can cause Bcl-2 protein overexpression. 26 The prognostic significance of Bcl-2 expression is also controversial, and comparison between different studies is hampered by the choice of different cut-offs of positive cells, and by the variability of treatments. In patients treated with R-CHOP, Bcl-2 protein did not correlate with outcome, 5,27 since the addition of rituximab seemed to improve survival of Bcl-2-positive patients, [28][29][30] apparently eliminating the gap between Bcl-2-positive and Bcl-2-negative patients found in the pre-rituximab era. This result does, however, appear to be contradicted in a very recent study in which Bcl-2 expression in GCB-DLBCL was associated with poorer outcome. 22 The goal of this study was to investigate the prognostic value of BCL2 gene aberrations and Bcl-2 expression in a large number of patients with de novo DLBCL, uniformly treated with R-CHOP, for whom MYC and GEP characterization was available. Design and Methods PatientsWe studied 327 cases of previously untreated de novo DLBCL, diagnosed between January 2002 and October 2009, and collected as part of the International DLBCL Rituxan-CHOP Consortium Program Study. These cases were analyzed for Bcl-2 protein expression, and BCL2 and MYC gene abnormalities, and gene expression profiling (GEP) was performed. All cases were reviewed by a group of hematopathologists (SMM, MAP, MBM, AT, and KHY), and the diagnoses were confirmed based on World Health Organization classification criteria. Patients with transformation from low grade lymphoma, those with composite follicular lymphoma, primary mediastinal large B-cell lymphoma, primary cutaneous and primary central nervous system DLBCL were excluded from the analysis due to the unique biological features of these types of lymphoma. All pat...

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK LBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma with characteristic ALK rearrangements. Diagnosis of ALK LBCL can be challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. The purpose of this study is to further explore the clinicopathologic features of ALK LBCL to ensure the awareness and accurate diagnosis of this entity. We retrospectively reviewed the data from 26 cases in our institutions and additional 108 cases from the literature. ALK LBCL typically occurred in the lymph nodes of young and middle-aged, immunocompetent patients. The medium age was 35 years with a male to female ratio of 3.5:1. Vast majority of cases showed immunoblastic and/or plasmablastic morphology. All cases expressed ALK protein with a cytoplasmic granular pattern in most of them. Common B-cell markers (CD20, CD79a, and PAX5) were typically negative, but the tumor cells mostly expressed 2 B-cell transcriptional factors, BOB1 and OCT2. The 5-year overall survival (OS) was 34%, and the median survival was 1.83 years. In patients with stage III/IV disease, the 5-year OS was only 8%. Moreover, patients below 35 years of age had a significantly better OS than those aged 35 years or above.