Division of Hematology-Oncology and the University of Michigan Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Blood. 2013 Feb 7;121(6):905-17. doi: 10.1182/blood-2012-03-416503. Epub 2012 Oct 31.
The leukemia stem cell (LSC) hypothesis proposes that a subset of cells in the bulk leukemia population propagates the leukemia.We tested the LSC hypothesis in a mouse model of Notch-induced T-cell acute lymphoblastic leukemia (T-ALL) in which the tumor cells were largely CD4+ CD8+ T cells. LSC activity was enriched but rare in the CD8+ CD4 HSA(hi) immature single-positive T-cell subset. Although our murine T-ALL model relies on transduction of HSCs, we were unable to isolate Notch-activated HSCs to test for LSC activity. Further analysis showed that Notch activation in HSCs caused an initial expansion of hematopoietic and T-cell progenitors and loss of stem cell quiescence, which was followed by progressive loss of long-term HSCs and T-cell production over several weeks. Similar results were obtained in a conditional transgenic model in which Notch activation is induced in HSCs by Cre recombinase. We conclude that although supraphysiologic Notch signaling in HSCs promotes LSC activity in T-cell progenitors, it extinguishes self-renewal of LT-HSCs. These results provide further evidence for therapeutically targeting T-cell progenitors in T-ALL while also underscoring the need to tightly regulate Notch signaling to expand normal HSC populations for clinical applications.
白血病干细胞 (LSC) 假说提出，在大量白血病群体中，有一部分细胞会促进白血病的发生。我们在一种由 Notch 诱导的 T 细胞急性淋巴细胞白血病（T-ALL）的小鼠模型中检验了 LSC 假说，该模型中的肿瘤细胞主要是 CD4+ CD8+ T 细胞。LSC 活性在 CD8+ CD4 HSA（高）幼稚单阳性 T 细胞亚群中虽然富集但却很罕见。尽管我们的小鼠 T-ALL 模型依赖于 HSC 的转导，但我们无法分离 Notch 激活的 HSC 来检测 LSC 活性。进一步的分析表明，HSC 中的 Notch 激活导致造血和 T 细胞祖细胞的初始扩增以及干细胞静止状态的丧失，随后在数周内逐渐丧失长期 HSC 和 T 细胞的产生。在通过 Cre 重组酶诱导 HSCs 中 Notch 激活的条件性转基因模型中也获得了类似的结果。我们得出结论，尽管 HSCs 中超生理的 Notch 信号会促进 T 细胞祖细胞中的 LSC 活性，但它会使 LT-HSC 的自我更新能力丧失。这些结果为在 T-ALL 中靶向治疗 T 细胞祖细胞提供了进一步的证据，同时也强调了需要严格调控 Notch 信号以扩增正常 HSC 群体以用于临床应用。
