Long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis, exemplified by the recent finding that lncRNA maternally expressed gene 3 (MEG3) inhibits tumor growth in a p53-dependent manner. Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults, and TP53 mutations or loss are frequently detected in patients with therapy-related AML or AML with complex karyotype. Here, we reveal that MEG3 is significantly downregulated in AML and suppresses leukemogenesis not only in a p53-dependent, but also a p53-independent manner. In addition, MEG3 is proven to be transcriptionally activated by Wilms’ tumor 1 (WT1), dysregulation of which by epigenetic silencing or mutations is causally involved in AML. Therefore MEG3 is identified as a novel target of the WT1 molecule. Ten–eleven translocation-2 (TET2) mutations frequently occur in AML and significantly promote leukemogenesis of this disorder. In our study, TET2, acting as a cofactor of WT1, increases MEG3 expression. Taken together, our work demonstrates that TET2 dysregulated WT1-MEG3 axis significantly promotes AML leukemogenesis, paving a new avenue for diagnosis and treatment of AML patients.

Purpose Bispecific antibodies (BsAbs) have emerged as a leading drug class for cancer therapy and are becoming increasingly of interest for therapeutic applications. As of April 2020, over 123 BsAbs are under clinical evaluation for use in oncology (including the two marketed BsAbs Blinatumomab and Catumaxomab). The majority (82 of 123) of BsAbs under clinical evaluation can be categorized as bispecific immune cell engager whereas a second less well-discussed subclass of BsAbs targets two tumor-associated antigens (TAAs). In this review, we summarize the clinical development of dual TAAs targeting BsAbs and provide an overview of critical considerations when designing dual TAA targeting BsAbs. Methods Herein the relevant literature and clinical trials published in English until April 1st 2020 were searched using PubMed and ClinicalTrials.gov database. BsAbs were considered to be active in clinic if their clinical trials were not terminated, withdrawn or completed before 2018 without reporting results. Data missed by searching ClinicalTrials.gov was manually curated. Results Dual TAAs targeting BsAbs offer several advantages including increased tumor selectivity, potential to concurrently modulate two functional pathways in the tumor cell and may yield improved payload delivery. Conclusions Dual TAAs targeting BsAbs represent a valuable class of biologics and early stage clinical studies have demonstrated promising anti-tumor efficacy in both hematologic malignancies and solid tumors.

Glioblastoma (GBM) is the most common malignant adult brain tumor generally associated with high level of cellular heterogeneity and a dismal prognosis. Long noncoding RNAs (lncRNAs) are emerging as novel mediators of tumorigenesis. Recently developed single-cell RNA-seq provides an unprecedented way for analysis of the cell-to-cell variability in lncRNA expression profiles. Here we comprehensively examined the expression patterns of 2,003 lncRNAs in 380 cells from five primary GBMs and two glioblastoma stem-like cell (GSC) lines. Employing the self-organizing maps, we displayed the landscape of the lncRNA expression dynamics for individual cells. Further analyses revealed heterogeneous nature of lncRNA in abundance and splicing patterns. Moreover, lncRNA expression variation is also ubiquitously present in the established GSC lines composed of seemingly identical cells. Through comparative analysis of GSC and corresponding differentiated cell cultures, we defined a stemness signature by the set of 31 differentially expressed lncRNAs, which can disclose stemness gradients in five tumors. Additionally, based on known classifier lncRNAs for molecular subtypes, each tumor was found to comprise individual cells representing four subtypes. Our systematic characterization of lncRNA expression heterogeneity lays the foundation for future efforts to further understand the function of lncRNA, develop valuable biomarkers, and enhance knowledge of GBM biology.

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The B7 family, and their receptors, the CD28 family, are major immune checkpoints that regulate T-cell activation and function. In the present study, we explore the role of two B7 immune-checkpoints: HERV-H LTR-Associating Protein 2 (HHLA2) and B7 Family Member, H4 (B7x), in the progression of gastrointestinal and pancreatic neuroendocrine tumors (GINETs and PNETs). We demonstrated that both HHLA2 and B7x were expressed to a high degree in human GINETs and PNETs. We determined that the expression of B7x and HHLA2 correlates with higher grade and higher incidence of nodal and distant spread. Furthermore, we confirmed that HIF-1 overexpression is associated with the upregulation of B7x both in our in vivo (animal model) and in vitro (cell culture) models. When grown in vitro, islet tumor β-cells lack B7x expression, unless cultured under hypoxic conditions, which results in both hypoxia inducible factor 1 subunit alpha (HIF-1α) and B7x upregulation. In vivo, we demonstrated that Men1/B7x double knockout (KO) mice (with loss of B7x expression) exhibited decreased islet β-cell proliferation and tumor transformation accompanied by increased T-cell infiltration compared with Men1 single knockout mice. We have also shown that systemic administration of a B7x mAb to our Men1 KO mice with PNETs promotes an antitumor response mediated by increased T-cell infiltration. These findings suggest that B7x may be a critical mediator of tumor immunity in the tumor microenvironment of NETs. Therefore, targeting B7x offers an attractive strategy for the immunotherapy of patients suffering from NETs.