MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny
MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny
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DOI：
10.1038/leu.2012.343
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发表时间：
2013-05-01
期刊：
影响因子：
11.4
通讯作者：
Schuringa, J. J.
中科院分区：
文献类型：
--
作者：
Horton, S. J.;Jaques, J.;Schuringa, J. J.
MLL-AF9融合基因在婴儿中与髓系和淋巴系的侵袭性白血病有关，而在成年人中，这种易位主要与急性髓系白血病有关。这些观察表明，胎儿组织和成人组织在白血病发生的“起源细胞”方面存在差异。在这里，我们表明，依赖于外部线索，人类新生儿CD34(+)细胞很容易在MLL-AF9表达时沿着髓系或淋巴系永生化，并在免疫低下的小鼠中引起主要的淋巴细胞性白血病。相比之下，成人骨髓CD34(+)细胞的永生化更难实现，而且更偏向于髓系，即使在纯化的造血干细胞(HSCs)中表达MLL-AF9。转录组分析证实，在表达MLL-AF9的细胞中，HSC丰富，但没有祖细胞基因特征。尽管在成人细胞中没有观察到表达MLL-AF9的新生儿细胞，但表达MLL-AF9的新生儿细胞富含与预后不良、对化疗药物耐药和MYC信号有关的基因特征。这些结果表明，新生细胞比成年细胞更容易由MLL-AF9介导的永生化，这表明除了外在提示外，起源细胞的内在属性决定了永生化细胞的谱系。
The MLL-AF9 fusion gene is associated with aggressive leukemias of both the myeloid and lymphoid lineage in infants, whereas in adults, this translocation is mainly associated with acute myeloid leukemia. These observations suggest that differences exist between fetal and adult tissues in terms of the 'cell of origin' from which the leukemia develops. Here we show that depending on extrinsic cues, human neonatal CD34(+) cells are readily immortalized along either the myeloid or lymphoid lineage upon MLL-AF9 expression and give rise to mainly lymphoid leukemia in immunocompromised mice. In contrast, immortalization of adult bone marrow CD34(+) cells is more difficult to achieve and is myeloid-biased, even when MLL-AF9 is expressed in purified hematopoietic stem cells (HSCs). Transcriptome analysis identified enrichment of HSC but not progenitor gene signatures in MLL-AF9-expressing cells. Although not observed in adult cells, neonatal cells expressing MLL-AF9 were enriched for gene signatures associated with poor prognosis, resistance to chemotherapeutic agents and MYC signaling. These results indicate that neonatal cells are inherently more prone to MLL-AF9-mediated immortalization than adult cells and suggest that intrinsic properties of the cell of origin, in addition to extrinsic cues, dictate lineage of the immortalized cell.