While cancer stem cells are well established in certain hematologic and solid malignancies, their existence in T cell lymphoma is unclear and the origin of disease is not fully understood. To examine the existence of lymphoma stem cells, we utilized a mouse model of anaplastic large cell lymphoma. Established NPM-ALK⁺ lymphomas contained heterogeneous cell populations ranging from mature T cells to undifferentiated hematopoietic stem cells. Interestingly, CD4⁻/CD8⁻ double negative (DN) lymphoma cells aberrantly expressed the T cell receptor α/β chain. Serial transplantation of sorted CD4/CD8 and DN lymphoma subpopulations identified lymphoma stem cells within the DN3/DN4 T cell population, whereas all other subpopulations failed to establish serial lymphomas. Moreover, transplanted lymphoma DN3/DN4 T cells were able to differentiate and gave rise to mature lymphoma T cells. Gene expression analyses unmasked stem-cell-like transcriptional regulation of the identified lymphoma stem cell population. Furthermore, these lymphoma stem cells are characterized by low CD30 expression levels, which might contribute to limited long-term therapeutic success in patients treated with anti-CD30-targeted therapies. In summary, our results highlight the existence of a lymphoma stem cell population in a NPM-ALK-driven CD30⁺ mouse model, thereby giving the opportunity to test innovative treatment strategies developed to eradicate the origin of disease.

虽然癌症干细胞在某些血液和实体恶性肿瘤中得到了很好的建立，但它们在 T 细胞淋巴瘤中的存在尚不清楚，而且疾病的起源也没有完全了解。为了检查淋巴瘤干细胞的存在，我们利用了间变性大细胞淋巴瘤的小鼠模型。已建立的 NPM-ALK ⁺淋巴瘤包含从成熟 T 细胞到未分化造血干细胞的异质细胞群。有趣的是，CD4 ^- /CD8 ^-双阴性 (DN) 淋巴瘤细胞异常表达 T 细胞受体 α/β 链。分选的 CD4/CD8 和 DN 淋巴瘤亚群的连续移植在 DN3/DN4 T 细胞群中鉴定出淋巴瘤干细胞，而所有其他亚群未能建立连续淋巴瘤。此外，移植的淋巴瘤 DN3/DN4 T 细胞能够分化并产生成熟的淋巴瘤 T 细胞。基因表达分析了已鉴定的淋巴瘤干细胞群的未掩蔽干细胞样转录调控。此外，这些淋巴瘤干细胞的特点是 CD30 表达水平低，这可能会限制接受抗 CD30 靶向治疗的患者的长期治疗成功率。总之，我们的结果强调了 NPM-ALK 驱动的 CD30 中淋巴瘤干细胞群的存在⁺小鼠模型，从而有机会测试为根除疾病起源而开发的创新治疗策略。