MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny.
Publication year
2013Source
Leukemia, 27, 5, (2013), pp. 1116-1126ISSN
Annotation
1 april 2013
Publication type
Article / Letter to editor

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Organization
Haematology
Journal title
Leukemia
Volume
vol. 27
Issue
iss. 5
Page start
p. 1116
Page end
p. 1126
Subject
ONCOL 3: Translational researchAbstract
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.
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- Academic publications [204968]
- Faculty of Medical Sciences [81049]
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