State Key Laboratory of Experimental Hematology.
Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin.
Haematologica. 2019 Oct;104(10):1950-1961. doi: 10.3324/haematol.2018.214593. Epub 2019 Feb 21.
Normal hematopoiesis can be disrupted by the leukemic bone marrow microenvironment, which leads to cytopenia-associated symptoms including anemia, hemorrhage and infection. Thrombocytopenia is a major and sometimes fatal complication in patients with acute leukemia. However, the mechanisms underlying defective thrombopoiesis in leukemia have not been fully elucidated. In the steady state, platelets are continuously produced by megakaryocytes. Using an -induced acute myeloid leukemia mouse model, we demonstrated a preserved number and proportion of megakaryocyte-primed hematopoietic stem cell subsets, but weakened megakaryocytic differentiation via both canonical and non-canonical routes. This primarily accounted for the dramatic reduction of megakaryocytic progenitors observed in acute myeloid leukemia bone marrow and a severe disruption of the maturation of megakaryocytes. Additionally, we discovered overproduction of interleukin-4 from bone marrow endothelial cells in acute myeloid leukemia and observed inhibitory effects of interleukin-4 throughout the process of megakaryopoiesis Furthermore, we observed that inhibition of interleukin-4 in combination with induction chemotherapy not only promoted recovery of platelet counts, but also prolonged the duration of remission in our acute myeloid leukemia mouse model. Our study elucidates a new link between interleukin-4 signaling and defective megakaryopoiesis in acute myeloid leukemia bone marrow, thereby offering a potential therapeutic target in acute myeloid leukemia.
正常的造血过程可能会受到白血病骨髓微环境的干扰，导致与细胞减少相关的症状，包括贫血、出血和感染。血小板减少症是急性白血病患者的主要且有时是致命的并发症。然而，白血病中血小板生成缺陷的机制尚未完全阐明。在稳态下，血小板由巨核细胞不断产生。通过诱导的急性髓系白血病小鼠模型，我们证明了巨核细胞前体造血干细胞亚群的数量和比例保持不变，但通过经典和非经典途径，巨核细胞分化减弱。这主要导致急性髓系白血病骨髓中巨核细胞前体的数量急剧减少，以及巨核细胞成熟的严重破坏。此外，我们发现急性髓系白血病骨髓中的骨髓内皮细胞过度产生白细胞介素-4，并观察到白细胞介素-4在整个巨核细胞生成过程中的抑制作用。此外，我们观察到白细胞介素-4抑制与诱导化疗相结合不仅促进血小板计数的恢复，而且延长了我们的急性髓系白血病小鼠模型的缓解期持续时间。我们的研究阐明了白细胞介素-4信号与急性髓系白血病骨髓中缺陷性巨核细胞生成之间的新联系，从而为急性髓系白血病提供了一个潜在的治疗靶点。
