2020年 · 第02卷第02期

Platelets play vital roles in hemostasis, inflammation, and vascular biology. Platelets are also active participants in the immune responses. As vertebrates, zebrafish have a highly conserved hematopoietic system in the developmental, cellular, functional, biochemical, and genetic levels with mammals. Thrombocytes in zebrafish are functional homologs of mammalian platelets. Here, we summarized thrombocyte development, function, and related research techniques in zebrafish, and reviewed available zebrafish models of platelet-associated disorders, including congenital amegakaryocytic thrombocytopenia, inherited thrombocytopenia, essential thrombocythemia, and blood coagulation disorders such as gray platelet syndrome. These elegant zebrafish models and methods are crucial for understanding the molecular and genetic mechanisms of thrombocyte development and function, and provide deep insights into related human disease pathophysiology and drug development.

Hematological malignancies, including leukemia and lymphoma, consist a group of highly heterogeneous neoplasms characterized by numerous genetic lesions specific for the type of the disease. In order to understand, the role of a particular alteration in the development of a malignancy functional studies have to be carried out in vitro, in cell lines derived from primary cancer cells. Further efforts to understand the mechanisms underlying blood disorders including malignant transformation and progression relies on model organism research. Numerous transgenic mouse models, carrying human oncogenes have been generated resembling distinct types of hematological disorders. Recent technological advances revolutionized the generation of animal models making it much easier, faster, and precise. The introduction of the CRISPR-Cas9 technology allows for rapid generation of novel knockout or transgenic animals, and the development of conditional site- and time-specific Cre-Lox gene targeting technology, allows studying the function of genes which are relevant to normal hematopoiesis and development of hematological malignancies, but lethal when knocked out in embryonic cells. Besides the studies on gene function, mouse models of human leukemia allow for discovery and testing of novel antileukemic drugs. These new technologies are deepening our understanding of disease pathophysiology and treatment resistance, as well as are leading to novel therapeutic strategies for improved outcomes in patients.

Acute myeloid leukemia (AML) has been shown to undergo multiple acquired mutations in hematopoietic cell lineages over years before becoming clinically apparent. The early stage of AML (before it becomes clinically recognizable) may be characterized by acquisition of some, but not all, leukemia-related somatic mutations in hematopoietic stem cells (HSCs). The physiological roles of these mutations remain puzzling. These HSCs have been termed as preleukemic HSCs. However, those frequent acquired somatic mutations are also found in healthy aging adults, namely, "age-related clonal hematopoiesis." Multiple studies have demonstrated that the preleukemic HSCs survive through chemotherapy and then contribute to the relapse and the development of de novo AML. Whether preleukemic HSCs should be targeted or whether a preventive therapy should be considered for those individuals remains to be determined. This article aims to shed light on this special subject and to discuss the roles of preleukemic HSCs in leukemogenesis.