Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells
Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells
复制标题
DOI：
10.1038/ng1898
复制
发表时间：
2006-11-01
期刊：
影响因子：
30.8
通讯作者：
Tenen, Daniel G.
中科院分区：
文献类型：
--
作者：
Steidl, Ulrich;Rosenbauer, Frank;Tenen, Daniel G.
转录因子 PU.1（由 Sfpi1 编码）的敲低会导致小鼠急性髓系白血病 (AML)。我们检查了 PU.1 被敲低的白血病前期造血干细胞 (HSC) 的转录组（称为“PU.1 敲低 HSC”），以鉴定恶性转化之前的转录变化。转录因子 c-Jun 和 JunB 是下调最多的目标之一。白血病前期细胞中 c-Jun 表达的恢复挽救了 PU.1 敲低引发的骨髓单核细胞分化阻滞。白血病阶段的 JunB 慢病毒恢复导致白血病自我更新能力丧失，并在移植了白血病 PU.1 敲低细胞的 NOD-SCID 小鼠中预防白血病。对患有 AML 的人类个体的检查证实了 PU.1 和 JunB 下调之间的相关性。这些结果描绘了 PU.1 敲低 HSC 中白血病转化之前的转录模式，并证明 c-Jun 和 JunB 水平降低通过阻止分化和增加自我更新而有助于 PU.1 敲低诱导的 AML 的发展。因此，检查 HSC 中受干扰的基因表达可以识别其失调对于白血病干细胞功能至关重要的基因，并且这些基因是治疗干预的目标。
Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as `PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. Restoration of c-Jun expression in preleukemic cells rescued the PU.1 knockdown initiated myelomonocytic differentiation block. Lentiviral restoration of JunB at the leukemic stage led to loss of leukemic self-renewal capacity and prevented leukemia in NOD-SCID mice into which leukemic PU.1-knockdown cells were transplanted. Examination of human individuals with AML confirmed the correlation between PU.1 and JunB downregulation. These results delineate a transcriptional pattern that precedes leukemic transformation in PU.1- knockdown HSCs and demonstrate that decreased levels of c-Jun and JunB contribute to the development of PU.1 knockdown-induced AML by blocking differentiation and increasing self-renewal. Therefore, examination of disturbed gene expression in HSCs can identify genes whose dysregulation is essential for leukemic stem cell function and that are targets for therapeutic interventions.