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Oncogenes, Fusion Genes and Tumor Suppressor Genes

MLL–AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny

Leukemia volume 27, pages 1116–1126 (2013)Cite this article

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Abstract

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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Acknowledgements

We greatly appreciate the help of Dr JJ Erwich and Dr A van Loon and colleagues (Departments of Obstetrics, University Medical Center Groningen and Martini Hospital Groningen) for collecting cord blood and Dr AG Veldhuizen (Department of Orthopedic surgery, University Medical Center Groningen) for collecting BM. We would also like to thank Kirin for supplying TPO and Amgen for supplying Flt-3L and SCF. Many thanks to Henk Moes, Geert Mesander and Roelof Jan van der Lei for help with cell sorting. This work is supported by grants from Leukemia and Lymphoma Research UK (2007-07039) to SJH, NWO-VENI (2004) to JJS, NWO-VIDI (2008) to JJS, KWF (RUG 2009-4275) to JJS and EV, Interlink and AIRC to GM.

Author contributions

SJH, JJ, MM and CW performed experiments and analyzed data; EV, GH, GM and JJS analyzed and discussed data; JVD. performed transcriptome and GSEA analyses; SJH and JJS designed the experiments, analyzed and discussed data and wrote the manuscript.

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  1. S J Horton

    Present address: 3Current address: Department of Hematology, Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 OXY, UK.,

Authors and Affiliations

  1. Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    S J Horton, J Jaques, C Woolthuis, J van Dijk, G Huls, E Vellenga & J J Schuringa

  2. University of Catanzaro, Catanzaro, Italy

    M Mesuraca & G Morrone

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Horton, S., Jaques, J., Woolthuis, C. et al. MLL–AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny. Leukemia 27, 1116–1126 (2013). https://doi.org/10.1038/leu.2012.343

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