Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells

Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs), creating a preleukemic stem cell (PLSC). Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC). Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM), but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus. We studied PLSC linked to thymic lymphomas. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Following BM transplantation, we found that MSH2-/- BM cells from young mice are able to fully reconstitute multiple hematopoietic lineages of lethally irradiated wild-type recipients. However, all recipients developed thymic lymphomas within three and four months post transplantation. Transplantation of different fractions of BM cells or thymocytes from young health MSH2-/- mice showed that an HSC enriched fraction always reconstituted hematopoiesis followed by lymphoma development. In addition, lymphomas did not occur in thymectomized recipients of MSH2-/- BM. These results suggest that HSCs with DNA repair defects such as MSH2-/- are PLSCs because they retain hematopoietic function, but also carry an obligate lymphomagenic potential within their T-cell progeny that is dependent on the thymic microenvironment.

造血系统恶性肿瘤的转化事件可发生于不同发育阶段，但其初始突变起源于造血干细胞（hematopoietic stem cells，HSCs），进而形成白血病前干细胞（preleukemic stem cell，PLSC）。后续在干细胞或祖细胞层面发生的继发突变，可将白血病前干细胞转化为淋巴瘤/白血病起始细胞（lymphoma/leukemia initiating cells，LIC）。
既往学界认为胸腺淋巴瘤起源于发育中的胸腺细胞。T细胞祖细胞由骨髓（bone marrow，BM）中的造血干细胞生成，但T细胞的成熟、增殖以及T细胞淋巴瘤发生，均依赖于胸腺内的调控机制与微环境。
本研究聚焦于与胸腺淋巴瘤相关的白血病前干细胞。本研究采用MSH2-/-小鼠作为动物模型，探究白血病前干细胞的存在性，及其向淋巴瘤/白血病起始细胞的演化进程。
骨髓移植实验结果显示：年轻MSH2-/-小鼠的骨髓细胞可完全重建致死剂量照射的野生型受体小鼠的多系造血谱系，但所有受体小鼠均在移植后3至4个月内出现胸腺淋巴瘤。
对年轻健康MSH2-/-小鼠的骨髓细胞或胸腺细胞进行分群移植实验表明，富集造血干细胞的细胞组分始终可重建造血功能，并后续引发淋巴瘤发生。此外，接受MSH2-/-骨髓移植的胸腺切除受体小鼠未出现淋巴瘤。
上述结果提示：携带MSH2-/-等DNA修复缺陷的造血干细胞即为白血病前干细胞——这类细胞既保留正常造血功能，同时在其T细胞子代中存在依赖胸腺微环境的致淋巴瘤固有潜能。