Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Leukemia. 2013 Apr;27(5):1116-26. doi: 10.1038/leu.2012.343. Epub 2012 Nov 26.
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.
MLL-AF9 融合基因与婴儿的髓系和淋巴系侵袭性白血病有关，而在成人中，这种易位主要与急性髓系白血病有关。这些观察结果表明，胎儿和成人组织在白血病起源的“细胞”方面存在差异。在这里，我们表明，取决于外在线索，人新生儿 CD34+细胞在表达 MLL-AF9 后很容易沿着髓系或淋巴系无限增殖，并在免疫缺陷小鼠中主要引发淋巴性白血病。相比之下，成人骨髓 CD34+细胞的永生化更难实现，并且偏向髓系，即使在纯化的造血干细胞 (HSCs) 中表达 MLL-AF9 也是如此。转录组分析鉴定出在表达 MLL-AF9 的细胞中富集了 HSC 而不是祖细胞基因特征。尽管在成人细胞中未观察到，但表达 MLL-AF9 的新生儿细胞富含与预后不良、对化疗药物和 MYC 信号的抗性相关的基因特征。这些结果表明，新生儿细胞比成人细胞更容易受到 MLL-AF9 介导的永生化，并且表明除了外在线索之外，起源细胞的内在特性决定了永生化细胞的谱系。
