Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease
Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease
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DOI：
10.1182/blood.v100.6.2046.h81802002046_2046_2055
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发表时间：
2002-09-15
期刊：
影响因子：
20.3
通讯作者：
Villeval, JL
中科院分区：
文献类型：
--
作者：
Dorsch, M;Zheng, G;Villeval, JL
Notch信号传导在许多发育系统（包括造血系统）中的细胞命运决定中起关键作用。我们和其他人最近克隆了一种名为Delta 4的新型Notch配体。在这项研究中，我们显示了逆转录病毒介导的Delta 4在造血细胞中异位表达的效果。移植表达Delta 4的骨髓细胞的致死辐射小鼠最初患有白细胞减少症和血小板减少症。虽然所有谱系都受到影响，但B细胞和血小板的缺陷是最持久和最严重的。移植后不久，CD 4（+）CD 8（+）细胞迅速扩增。CD 4（+）CD 8（+）细胞逐渐侵入分析的所有组织，但胸腺除外，令人惊讶的是，胸腺是萎缩的。CD 4（+）CD 8（+）细胞主要为非Delta 4转导细胞，强烈表明该疾病不是细胞自主的。移植后约15周，小鼠死于这种严重的淋巴组织增生性疾病，这种疾病在晚期疾病中不能移植到第二受体中。用可溶性形式的Delta 4转导的小鼠表现得像对照小鼠。早期造血发育的表征显示，Delta 4表达损害了第12天脾集落形成单位（CFU-Ss）的形成，并且在更大程度上损害了前CFU-Ss的形成。未观察到对骨髓集落形成细胞（CFU-Cs）的影响，表明Delta 4特异性作用于最早的造血干细胞区室。这些结果表明，造血细胞中Delta 4的组成型表达损害B细胞、血小板和早期干细胞的发育，并诱导致死性淋巴增生性疾病。
Notch signaling plays a critical role in cell fate determination in many developmental systems, including the hematopoietic system. We and others have recently cloned a novel Notch ligand called Delta4. In this study, we show the effect of retrovirus-mediated ectopic expression of Delta4 in hematopoietic cells. Lethally irradiated mice transplanted with bone marrow cells expressing Delta4 initially suffered from leukopenia and thrombocytopenia. Although all lineages were affected, the deficit in B cells and platelets was the most durable and profound. A rapid expansion of CD4(+)CD8(+) cells occurred shortly after transplantation. CD4(+)CD8(+) cells progressively invaded all tissues analyzed except the thymus, which surprisingly was atrophic. CD4(+)CD8(+) cells were mainly non-Delta4-transduced cells, strongly suggesting that the disease was not cell autonomous. Around 15 weeks after transplantation, mice died from this severe lymphoproliferative disorder, which was not transplantable in late-stage disease into secondary recipients. Mice transduced with a soluble form of Delta4 behaved like control mice. Characterization of early hematopoietic development revealed that Delta4 expression impaired formation of day-12 spleen colony-forming units (CFU-Ss) and, to a greater extent, pre-CFU-Ss. No effect was observed on myeloid colony-forming cells (CFU-Cs), indicating that Delta4 specifically acted on the earliest hematopoietic stem cell compartment. These results show that constitutive expression of Delta4 in hematopoietic cells impairs the development of B cells, platelets, and early stem cells and induces a lethal lymphoproliferative disease.