Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors
Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors
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DOI：
10.1016/j.stem.2007.05.019
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发表时间：
2007-09-01
期刊：
影响因子：
23.9
通讯作者：
Ernst, Patricia
中科院分区：
文献类型：
--
作者：
Jude, Craig D.;Climer, Leslie;Ernst, Patricia
混合系白血病（MLL）基因是胚胎造血干细胞（HSC）发育所必需的，但其在成人造血过程中的作用尚不清楚。使用诱导型敲除模型，我们证明Mll对于维持成体HSC和祖细胞是必不可少的，在Mll缺失的3周内发生致命的骨髓衰竭。MII缺陷细胞从混合的骨髓嵌合体中选择性丢失，表明它们即使在完整的骨髓环境中也不能自我更新。令人惊讶的是，缺乏MY的HSC表现出异位细胞周期进入，导致静止HSC的耗尽。相比之下，骨髓-红系祖细胞中的MII缺失导致增殖降低和对苦参碱诱导的细胞周期进入的响应降低。定向淋巴细胞和骨髓细胞不再需要MII，将造血的早期多能阶段定义为MII依赖性。这些研究表明，MII在造血系统内发挥选择性和独立性作用，维持HSC的静止并促进祖细胞的增殖。
The Mixed Lineage Leukemia (MLL) gene is essential for embryonic hematopoietic stem cell (HSC) development, but its role during adult hematopoiesis is unknown. Using an inducible knockout model, we demonstrate that Mll is essential for the maintenance of adult HSCs and progenitors, with fatal bone marrow failure occurring within 3 weeks of Mll deletion. Mll-deficient cells are selectively lost from mixed bone marrow chimeras, demonstrating their failure to self-renew even in an intact bone marrow environment. Surprisingly, HSCs lacking MY exhibit ectopic cell-cycle entry, resulting in the depletion of quiescent HSCs. In contrast, Mll deletion in myelo-erythroid progenitors results in reduced proliferation and reduced response to cytokine-induced cell-cycle entry. Committed lymphoid and myeloid cells no longer require Mll, defining the early multipotent stages of hematopoiesis as Mll dependent. These studies demonstrate that Mll plays selective and independent roles within the hematopoietic system, maintaining quiescence in HSCs and promoting proliferation in progenitors.