Curtis David J, Hall Mark A, Van Stekelenburg Leonie J, Robb Lorraine, Jane Stephen M, Begley C Glenn
Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.
Blood. 2004 May 1;103(9):3342-8. doi: 10.1182/blood-2003-09-3202. Epub 2004 Jan 15.
The stem cell leukemia (SCL) gene is essential for the development of hematopoietic stem cells in the embryo. Here, we used a conditional gene targeting approach to examine the function of SCL in adult hematopoietic stem cells (HSCs). Flow cytometry of bone marrow from SCL-deleted mice demonstrated a 4-fold increase in number of Lin(neg) c-kit(+) Sca-1(+) cells. Despite this increase in the number of phenotypic HSCs, competitive repopulation assays demonstrated a severe multilineage defect in repopulation capacity by SCL-deleted bone marrow cells. SCL-heterozygous cells also showed a mild repopulation defect, thus suggesting haploinsufficiency of SCL. The transplantation defect of SCL-deleted cells was observed within 4 weeks of transplantation, indicating a defect in a multipotent progenitor or short-term repopulating HSCs. Although the defect persisted in secondary transplants, it remained relatively stable, suggesting that SCL was not required for self-renewal of the HSCs. Generation of SCL-deleted cells within SCL-wild-type mice rescued the early repopulating defect. Together, our results suggest that SCL is required for the normal function of short-term repopulating HSCs.
干细胞白血病（SCL）基因对于胚胎中造血干细胞的发育至关重要。在此，我们采用条件性基因靶向方法来研究SCL在成体造血干细胞（HSCs）中的功能。对SCL缺失小鼠的骨髓进行流式细胞术分析显示，Lin(neg) c-kit(+) Sca-1(+)细胞数量增加了4倍。尽管表型HSCs数量有所增加，但竞争性再增殖试验表明，SCL缺失的骨髓细胞在再增殖能力方面存在严重的多谱系缺陷。SCL杂合细胞也表现出轻度的再增殖缺陷，这表明SCL存在单倍剂量不足。在移植后4周内就观察到了SCL缺失细胞的移植缺陷，这表明多能祖细胞或短期再增殖HSCs存在缺陷。尽管该缺陷在二次移植中持续存在，但相对稳定，这表明SCL并非HSCs自我更新所必需。在SCL野生型小鼠体内产生SCL缺失细胞可挽救早期再增殖缺陷。总之，我们的结果表明，SCL是短期再增殖HSCs正常功能所必需的。
