JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells
JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells
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DOI：
10.1016/j.cell.2004.10.010
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发表时间：
2004-10-29
期刊：
影响因子：
64.5
通讯作者：
Weissman, IL
中科院分区：
文献类型：
--
作者：
Passegué, E;Wagner, EF;Weissman, IL
AP-1转录因子JunB是骨髓生成的转录调节因子。出生后小鼠中JunB的失活导致类似于早期人类慢性髓细胞性白血病（CML）的骨髓增生性疾病（MPD）。在这里，我们表明JunB调节造血干细胞（HSC）的数量。JunB过表达降低了长期HSC（LT-HSC）的频率，而JunB失活特异性地扩大了LT-HSC和粒细胞/巨噬细胞祖细胞（GMP）的数量，导致慢性MPD。此外，我们证明了junB失活必须发生在LT-HSC中，而不是在骨髓生成的后期阶段，以诱导MPD，并且只有junB缺陷的LT-HSC能够将MPD移植到受体小鼠中。这些结果证明了JunB在正常和白血病造血中的干细胞特异性作用，并提供了白血病干细胞（LSC）可以在MPD小鼠模型中处于LT-HSC发育阶段的实验证据。
The AP-1 transcription factor JunB is a transcriptional regulator of myelopoiesis. Inactivation of JunB in postnatal mice results in a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML). Here, we show that JunB regulates the numbers of hematopoietic stem cells (HSC). JunB overexpression decreases the frequency of long-term HSC (LT-HSC), while JunB inactivation specifically expands the numbers of LT-HSC and granulocyte/macrophage progenitors (GMP) resulting in chronic MPD. Further, we demonstrate that junB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD and that only junB-deficient LT-HSC are capable of transplanting the MPD to recipient mice. These results demonstrate a stem cell-specific role for JunB in normal and leukemic hematopoiesis and provide experimental evidence that leukemic stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of MPD.