2019年 · 第01卷第02期

B lymphocytes produce antibodies under the stimulation of specific antigens, thereby exerting an immune effect. B cells identify antigens by their surface B cell receptor (BCR), which upon stimulation, directs the cell to activate and differentiate into antibody generating plasma cells. Activation of B cells via their BCRs involves signaling pathways that are tightly controlled by various regulators. In this review, we will discuss three major BCR mediated signaling pathways (the PLC-γ2 pathway, PI3K pathway and MAPK pathway) and related regulators, which were roughly divided into positive, negative and mutual-balanced regulators, and the specific regulators of the specific signaling pathway based on regulatory effects.

Hemophilia A and B are diseases caused by a single gene deficiency and are thus suitable for gene therapy. In recent clinical research, adeno-associated virus (AAV) was employed by several teams in the treatment of hemophilia A and B, and the outcomes were encouraging. In this review, we summarized the most recent research on the mechanism and application of AAV in the treatment of hemophilia, trying to analyze the advantages of AAV gene therapy and the main challenges in its clinical use. We also summarized the clinical trials involving hemophilia, especially those employing AAV gene therapy to treat hemophilia A and B, some of which have already been completed and some that are still ongoing. From the reports of the completed clinical trials, we tried to determine the correlations among AAV dose, AAV serotype, immune response, and gene expression time. Finally, taking into account the most recent studies investigating AAV capsid modification, transgene optimization, and AAV chaperones, we summarized the direction of basic research and clinical applications of AAV in the future.

The transcription of essentially the entire eukaryotic genome produces a huge amount of non-coding RNAs. Among them, long non-coding RNAs (lncRNAs) consist of a significant portion that widely exists across mammal genome, generating from high-throughput transcriptomic studies in the last decade. Although the functions of most lncRNAs remain to be further investigated, many of them have already been shown to play critical roles during normal development and disease conditions. Increasing evidence indicates that lncRNAs involve in versatile biological processes during erythroid proliferation and differentiation, including erythroid cell survival, heme metabolism, globin switching and regulation, erythroid enucleation, etc, via cis- or trans-mediated molecular mechanisms. In this review, we focus on recent advances regarding the functions and mechanisms of lncRNAs in normal erythropoiesis.

Hematopoietic stem cells (HSCs) are responsible for generating all blood cells throughout life. Apart from the role of HSCs in maintaining the homeostasis of blood cell production process, they must respond quickly to hematopoietic challenges, such as infection or blood loss. HSCs can be directly/indirectly activated and engage in blood formation for the acute needs in response to inflammation. Recent findings highlight the emerging role of inflammation signaling on HSC fate decision and shaping the hematopoietic system during aging. Here, we summarize recent studies identifying the changes in inflammation and their role in modulation of HSC function and discuss the interaction between inflammation and HSC biology in the contexts of aging and hematological malignancy.

The need for novel therapeutics against human cancers such as leukemias and solid tumors is well recognized. Human T cells are poised to make a fundamental change in the therapeutic approach. T-cell interaction with a tumor cell is a critical event and primarily driven by T-cell receptor (TCR) recognition of peptide in the pocket HLA. However, among TCR-based T-cell therapies, either TCR mismatching or the low density of major histocompatibility complex causes tumor cells to escape from the immune response. TCR molecules have low binding affinities, preventing their recognitions. Undoubtedly, antibody therapeutics is an effective treatment for cancer. As the new generation of monoclonal antibodies, TCR-like antibodies can mimic TCR recognition but are not susceptible for mechanisms of tumor evasion from the immune response. As chimeric antigen receptor (CAR) structure expressed on the surface of T cells, TCR-like antibodies can confer antigen specificity to T cells. The new TCR-like CAR may be important to drive new technologies of adoptive cell therapy, in particular, T-cell therapy, and open possibilities to target endogenous tumor-specific antigens.

Chimeric antigen receptor T (CAR-T) cells have emerged as novel and promising immune therapies for the treatment of multiple types of cancer in patients with hematological malignancies. There are several key components critical for development and application of CAR-T therapy. First, the design of CAR vectors can considerably affect several aspects of the physiological functions of these T cells. Moreover, despite the wide use of γ-retrovirus and lentivirus in mediating gene transfer into T cells, optimal CAR delivery systems are also being developed and evaluated. In addition, several classes of mouse models have been used to evaluate the efficacies of CAR-T cells; however, each model has its own limitations. Clinically, although surprising complete remission (CR) rates were observed in acute lymphoblastic leukemia (ALL), lymphoma, and multiple myeloma (MM), there is still a lack of specific targets for acute myeloid leukemia (AML). Leukemia relapse remains a major challenge, and its mechanism is presently under investigation. Cytokine release syndrome (CRS) and neurotoxicity are life-threatening adverse effects that need to be carefully treated. Several factors that compromise the activities of anti-solid cancer CAR-T cells have been recognized, and further improvements targeting these factors are the focus of the development of novel CAR-T cells. Overcoming the current hurdles will lead to optimal responses of CAR-T cells, thus paving the way for their wide clinical application.

Chimeric antigen receptor (CAR)-T-cell therapy has achieved significant success in the treatment of hematologic malignancies. However, treatment-related toxicity and side effects remain the major drawbacks. As an important effector cell in innate immunity, natural killer (NK) cells exert strong antitumor functions and have better application prospects in the immunotherapy of hematologic malignancies. Compared with T cells, NK cells exhibit several advantages such as MHC-independent recognition. CAR-modified NK (CAR-NK) cells may exhibit a better ability of killing tumor cells. Herein, we review mainly preclinical data related to the development of CAR-NK cells in treating blood cancers.

Erythropoiesis is a complex and sophisticated multi-stage process regulated by a variety of factors, including the transcription factor GATA1 and non-coding RNA. GATA1 is regarded as an essential transcriptional regulator promoting transcription of erythroid-specific genes—such as long non-coding RNAs (lncRNA). Here, we comprehensively screened lncRNAs that were potentially regulated by GATA1 in erythroid cells. We identified a novel lncRNA—PCED1B-AS1—and verified its role in promoting erythroid differentiation of K562 erythroid cells. We also predicted a model in which PCED1B-AS1 participates in erythroid differentiation via dynamic chromatin remodeling involving GATA1. The relationship between lncRNA and chromatin in the process of erythroid differentiation remains to be revealed, and in our study we have carried out preliminary explorations.