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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-05-1515.
Submitted May 24, 2002
Accepted December 12, 2002
Prenatal and postnatal myeloid cells demonstrate stepwise progression in the pathogenesis of MLL fusion gene leukemia
Jennifer J Johnson, Weili Chen, Wendy Hudson, Qing Yao, Marnie Taylor, Terence H Rabbitts, and John H Kersey*
University of Minnesota Cancer Center, Minneapolis, MN, USA
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
* Corresponding author; email: kerse001{at}umn.edu.
The steps to leukemia following an in-utero fusion of MLL (HRX, ALL-1) to a partner gene in humans are not known. Introduction of the Mll-AF9 fusion gene into embryonic stem cells results in leukemia in mice with cell-type specificity similar to humans. In this study we used myeloid colony assays, immunophenotyping and transplantation to evaluate myelopoiesis in Mll-AF9 mice. Colony assays demonstrated that both prenatal and postnatal Mll-AF9 tissues have significantly increased numbers of CD11b+/CD117+/Gr1+/- myeloid progenitor cells, often in compact clusters. The self-renewal capacity of prenatal myeloid progenitors was found to decrease following serial replating of colony-forming cells. In contrast, early postnatal myeloid progenitors increased following replating; however, the enhanced self renewal of early postnatal myeloid progenitor cells was limited and did not result in long term cell lines or leukemia in vivo. Unlimited replating, long-term CD11b/Gr1+ myeloid cell lines, and the ability to produce early leukemia in vivo in transplantation experiments were found only in mice with overt leukemia. Prenatal Mll-AF9 tissues had reduced total (mature and progenitor) CD11b/Gr1+ cells compared to wild type tissues. Colony replating, immunophenotyping, and cytochemistry suggest that any perturbation of cellular differentiation from the prenatal stage onwards is partial and largely reversible. We describe a novel informative in vitro and in vivo model system that permits study of the stages in the pathogenesis of Mll fusion gene leukemia, beginning in prenatal myeloid cells, progressing to a second stage in the postnatal period and finally resulting in overt leukemia in adult animals.
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