Long-term haematopoietic reconstitution by Trp53-/-p16Ink4a-/-p19Arf-/- multipotent progenitors
Long-term haematopoietic reconstitution by Trp53-/-p16Ink4a-/-p19Arf-/- multipotent progenitors
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DOI：
10.1038/nature06869
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发表时间：
2008-05-08
期刊：
影响因子：
64.8
通讯作者：
Clarke, Michael F.
中科院分区：
文献类型：
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作者：
Akala, Omobolaji O.;Park, In-Kyung;Clarke, Michael F.
造血是由一个等级系统维持的，在这个系统中，造血干细胞(HSCs)产生多能祖细胞，然后再分化为所有类型的成熟血细胞1。由于具有自我更新的能力，造血干细胞在生物体的整个生命周期中都能自我维持。然而，多能祖细胞缺乏自我更新的能力，因此它们的有丝分裂能力和扩张潜力是有限的，它们注定在有限数量的细胞分裂后最终停止增殖(1，2)。限制多能祖细胞和其他更成熟的祖细胞增殖能力的分子机制尚不完全清楚(2，3)。在这里，我们展示了来自Bmi1-p16(Ink4a)、p19(Arf)和trp53(三个突变小鼠；p16(Ink4a)和p19(Arf)是同一基因(也称为CDKN2a)编码不同蛋白质的可选读框的三个基因下游缺陷小鼠的骨髓细胞-能够长期重建血液的细胞大约增加了10倍。这种增加与表型c-kit(+)SCA-1(+)Flt3(+)CD150(-)CD48(-)Lin(-)的细胞获得长期重建能力有关，该表型定义了野生型小鼠的多能祖细胞(4-6)。三个突变的多能祖细胞对生长因子的反应模式类似于野生型多能祖细胞，而不是野生型HSCs。这些结果表明，p16(Ink4a)/p19(Arf)和Trp53在限制多能祖细胞的扩增潜能中起着核心作用。这些途径通常在癌症中受到抑制，这表明早期的祖细胞可以通过一种机制获得自我更新的能力，并通过进一步的致癌突变变得恶性。
Haematopoiesis is maintained by a hierarchical system where haematopoietic stem cells ( HSCs) give rise to multipotent progenitors, which in turn differentiate into all types of mature blood cells1. HSCs maintain themselves for the lifetime of the organism because of their ability to self- renew. However, multipotent progenitors lack the ability to self- renew, therefore their mitotic capacity and expansion potential are limited and they are destined to eventually stop proliferating after a finite number of cell divisions(1,2). The molecular mechanisms that limit the proliferation capacity of multipotent progenitors and other more mature progenitors are not fully understood(2,3). Here we show that bone marrow cells from mice deficient in three genes genetically downstream of Bmi1-p16(Ink4a), p19(Arf) and Trp53 ( triple mutant mice; p16(Ink4a) and p19(Arf) are alternative reading frames of the same gene ( also called Cdkn2a) that encode different proteins) - have an approximately 10-fold increase in cells able to reconstitute the blood long term. This increase is associated with the acquisition of long- term reconstitution capacity by cells of the phenotype c-kit(+)Sca-1(+)Flt3(+)CD150(-)CD48(-)Lin(-), which defines multipotent progenitors in wild- type mice(4-6). The pattern of triple mutant multipotent progenitor response to growth factors resembles that of wild- type multipotent progenitors but not wild- type HSCs. These results demonstrate that p16(Ink4a)/p19(Arf) and Trp53 have a central role in limiting the expansion potential of multipotent progenitors. These pathways are commonly repressed in cancer, suggesting a mechanism by which early progenitor cells could gain the ability to self- renew and become malignant with further oncogenic mutations.