Key Points Alternatively polarized macrophages are abundant constituents of the tumor microenvironment in T-cell lymphoproliferative disorders. GATA-3 expression identifies a subset of PTCL, NOS with a distinct cytokine profile and inferior survival.

Although previous studies have established a prominent role for HMGA1 (formerly HMG-I/Y) in aggressive human cancers, the role of HMGA2 (formerly HMGI-C) in malignant transformation has not been clearly defined. The HMGA gene family includes HMGA1, which encodes the HMGA1a and HMGA1b protein isoforms, and HMGA2, which encodes HMGA2. These chromatinbinding proteins function in transcriptional regulation and recent studies also suggest a role in cellular senescence. HMGA1 proteins also appear to participate in cell cycle regulation and malignant transformation, whereas HMGA2 has been implicated primarily in the pathogenesis of benign, mesenchymal tumors. Here, we show that overexpression of HMGA2 leads to a transformed phenotype in cultured lung cells derived from normal tissue. Conversely, inhibiting HMGA2 expression blocks the transformed phenotype in metastatic human non -small cell lung cancer cells. Moreover, we show that HMGA2 mRNA and protein are overexpressed in primary human lung cancers compared with normal tissue or indolent tumors. In addition, there is a statistically significant correlation between HMGA2 protein staining by immunohistochemical analysis and tumor grade (P < 0.001). Our results indicate that HMGA2 is an oncogene important in the pathogenesis of human lung cancer. Although additional studies with animal models are needed, these findings suggest that targeting HMGA2 could be therapeutically beneficial in lung cancer and other cancers characterized by increased HMGA2 expression. (Mol Cancer Res 2008;6(5):743 -50)

Although pancreatic ductal adenocarcinoma is a common and almost uniformly fatal cancer, little is known about the molecular events that lead to tumor progression. The high-mobility group A1 (HMGA1) protein is an architectural transcription factor that has been implicated in the pathogenesis and progression of diverse human cancers, including pancreatic ductal adenocarcinoma. Here, we investigated HMGA1 expression in pancreatic ductal adenocarcinoma cell lines and surgically resected tumors to determine if it could be a marker for more advanced disease. By real-time quantitative RT-PCR, we measured HMGA1a mRNA in cultured pancreatic ductal adenocarcinoma cell lines and found increased levels in all cancer cells compared to normal pancreatic tissue. To investigate HMGA1 in primary human tumors, we performed immunohistochemical analysis of 125 cases of pancreatic adenocarcinoma and 99 precursor lesions (PanIN 1–3). We found nuclear staining for HMGA1 in 98% of cases of pancreatic adenocarcinoma, but only 43% of cases of PanIN precursor lesions. Moreover, HMGA1 immunoreactivity correlates positively with decreased survival and advanced tumor and PanIN grade. These results suggest that HMGA1 promotes tumor progression in pancreatic ductal adenocarcinoma and could be a useful biomarker and rational therapeutic target in advanced disease.

Disease Overview: Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS). Diagnosis:The diagnosis of MF or SS requires the integration of clinical and histopathologic data.Risk-Adapted Therapy: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, skin-directed therapies are preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies. These include biologic-response modifiers, histone deacetylase (HDAC) inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Purpose T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T-cell specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR’s role in mediating resistance to chemotherapy. Experimental Design Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following T-cell receptor (TCR) engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines. Results Here we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3, and promotes chemotherapy resistance. Conclusions These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented activation of this signaling axis and overcame chemotherapy resistance.

Pancreatic ductal adenocarcinoma is a highly aggressive, lethal human malignancy that continues to elude successful treatment. Although most patients present with metastatic disease, the molecular pathways that underlie tumor progression and metastases are poorly understood. The high mobility group A2 (HMGA2) protein is an architectural transcription factor that has recently been implicated in the development and progression of malignant tumors. Here, we examined HMGA2 gene expression in pancreatic ductal adenocarcinoma to determine if it could be a marker for more advanced disease. By real time quantitative RT-PCR, we showed a marked increase in HMGA2 mRNA in two of three cultured pancreatic ductal adenocarcinoma cell lines compared to normal pancreatic tissue. Using tissue microarrays generated from 124 pancreatic ductal adenocarcinoma cases, we also assessed HMGA2 protein levels by immunohistochemical analysis. We found that HMGA2 nuclear immunoreactivity correlates positively with lymph node metastases and high tumor grade. Our results support a role for HMGA2 in the progression of pancreatic ductal adenocarcinoma and suggest that it could be a useful biomarker and rational therapeutic target in more advanced disease. Keywords: HMGA2; pancreatic ductal adenocarcinoma; oncogene; immunoreactivity Pancreatic ductal adenocarcinoma is a common, highly lethal malignancy accounting for over 30 000 deaths in America and 160 000 deaths worldwide each year. Unfortunately, current therapies, including surgery, chemotherapy, and radiation therapy, are largely ineffective and death rates closely parallel incidence rates. 1,2 Most patients with pancreatic ductal adenocarcinoma present with locally advanced or metastatic disease that renders them inoperable or limits the effectiveness of therapy. Moreover, even most patients with small lesions ultimately succumb to advanced disease with distant metastases, despite adjuvant therapy.These findings emphasize the importance of understanding the molecular events that lead to tumor progression. Although molecular events that contribute to the early development of pancreatic ductal adenocarcinoma have been elucidated, those that orchestrate tumor progression and metastasis are poorly understood.The HMGA genes encode a family of the high mobility group (HMG) proteins, which were discovered over 25 years ago as abundant, nonhistone chromatin binding proteins and named for their rapid electrophoretic mobility in polyacrylamide gels. [3][4][5] HMGA1a and HMGA1b protein isoforms result from alternative splicing of the HMGA1 mRNA, 3-5 whereas HMGA2 is encoded by the separate, but related gene, HMGA2. 6,7 All HMGA proteins contain three AT hook DNA-binding motifs that mediate binding to AT-rich regions in the minor groove of chromosomal DNA. 8,9 Once bound to DNA, the HMGA proteins recruit additional transcription factors, and in concert with these factors,

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• Whole-transcriptome sequencing reveals NPM1-TYK2 gene fusion in cutaneous CD30-positve lymphoproliferative disorders.• NPM1-TYK2 activates STAT signaling and is a therapeutic target in a subset of cutaneous CD30-positive lymphoproliferative disorders.The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n 5 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations. (Blood. 2014;124(25):3768-3771) IntroductionRecurrent chromosomal translocations frequently underlie the pathogenesis of several hematopoietic malignancies and often define molecular subtypes with distinct biological behavior. 1,2 Frequently, these translocations target tyrosine kinases resulting in constitutive activation and promotion of oncogenesis.3 Cutaneous CD30-positive lymphoproliferative disorders (LPD) represents a clinicopathologic spectrum including lymphomatoid papulosis (LYP) and primary cutaneous anaplastic large cell lymphoma (ALCL). 4 Gene fusions targeting tyrosine kinases underlying the pathogenesis of CD30-positive LPD have not been described. MethodsPatient biopsy samples were obtained with institutional review board approval. Complete description of methods and clinical samples are presented in the supplemental Methods (available on the Blood Web site). RNA was subjected to chimera analysis by producing paired-end libraries sequenced on the Illumina Genome Analyzer II. Sequencing data were analyzed using custom bioinformatics tools and Chimerascan software.5 Sequencing confirmation of NPM1-TYK2 fusion transcripts was achieved using SYBR Green-based quantitative real-time polymerase chain reaction (PCR) assays and Sanger sequencing of amplicons by reverse transcription PCR (RT-PCR (see supplemental "Materials"). Fluorescence in situ hybridization (FISH) was performed on tissue microarrays of primary patient samples using standard methods. TYK2 break-apart FISH and NPM1-TYK2 fusion FISH assays were designed to detect TYK2 rearrangements and NPM1-TYK2 fusions, respectively (see supplemental Methods). Immunohi...