Ding Jixin, Cardoso Angelo A, Yoshimoto Momoko, Kobayashi Michihiro
Department of Medicine, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States.
Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
Front Cell Dev Biol. 2021 Apr 29;9:634151. doi: 10.3389/fcell.2021.634151. eCollection 2021.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients. About 10-15% of pediatric ALL belong to T-cell ALL (T-ALL), which is characterized by aggressive expansion of immature T-lymphoblasts and is categorized as high-risk leukemia. Leukemia initiating cells represent a reservoir that is responsible for the initiation and propagation of leukemia. Its perinatal origin has been suggested in some childhood acute B-lymphoblastic and myeloblastic leukemias. Therefore, we hypothesized that child T-ALL initiating cells also exist during the perinatal period. In this study, T-ALL potential of the hematopoietic precursors was found in the para-aortic splanchnopleura (P-Sp) region, but not in the extraembryonic yolk sac (YS) of the mouse embryo at embryonic day 9.5. We overexpressed the Notch intracellular domain (NICD) in the P-Sp and YS cells and transplanted them into lethally irradiated mice. NICD-overexpressing P-Sp cells rapidly developed T-ALL while YS cells failed to display leukemia propagation despite successful NICD induction. These results suggest a possible role of fetal-derived T-cell precursors as leukemia-initiating cells.
急性淋巴细胞白血病（ALL）是儿科患者中最常见的恶性肿瘤。约10% - 15%的儿童ALL属于T细胞ALL（T-ALL），其特征为未成熟T淋巴母细胞的侵袭性扩增，被归类为高危白血病。白血病起始细胞是白血病起始和传播的根源。在一些儿童急性B淋巴细胞白血病和急性髓细胞白血病中，已有人提出其起源于围产期。因此，我们推测儿童T-ALL起始细胞在围产期也存在。在本研究中，于胚胎第9.5天在小鼠胚胎的主动脉旁脏壁中胚层（P-Sp）区域发现了造血前体的T-ALL潜能，但在胚外卵黄囊（YS）中未发现。我们在P-Sp和YS细胞中过表达Notch细胞内结构域（NICD），并将其移植到经致死剂量照射的小鼠体内。尽管成功诱导了NICD，但过表达NICD的P-Sp细胞迅速发展为T-ALL，而YS细胞未能显示白血病传播。这些结果提示胎儿来源的T细胞前体作为白血病起始细胞可能发挥的作用。
