Abstract
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.
Highlights
In the hematopoietic system, Notch signaling is essential for the commitment of multipotent hematopoietic progenitors (MPP) to the T-cell lineage and it supports cell growth, proliferation and survival at multiple stages of thymocyte development (Tanigaki and Honjo, 2007; Hozumi et al, 2008; Luis et al, 2016)
We demonstrated that E9.5 paraaortic splanchnopleura (P-Sp)-derived cells cocultured with OP9-DL1 possess T-Acute lymphoblastic leukemia (ALL)-initiating potential by overexpressing Notch intracellular domain (NICD)
We have recently shown the presence of T-precursors among VC+ckit+ HSC-precursors in E10.5 yolk sac (YS) and AGM region, which engrafted in the immunodeficient mice without co-culture (Kobayashi et al, 2019)
Summary
Notch signaling is essential for the commitment of multipotent hematopoietic progenitors (MPP) to the T-cell lineage and it supports cell growth, proliferation and survival at multiple stages of thymocyte development (Tanigaki and Honjo, 2007; Hozumi et al, 2008; Luis et al, 2016). The Loss-of-function mutations in FBXW7 are commonly found in T-ALL and result in inhibition of ubiquitin-mediated degradation of the activated form of Notch (Iacobucci and Mullighan, 2017; Karrman and Johansson, 2017). These mutations cause ligand independent activation and stability of the Notch intracellular domain (NICD), subsequently leading to the increased proliferation and survival of leukemic cells (Staal and Langerak, 2008). Activated Notch mutation plays a major pathogenetic role in human T-ALL
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