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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-05-1515.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3229-3235
NEOPLASIA
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
From the University of Minnesota Cancer Center,
Minneapolis; and Medical Research Council Laboratory of
Molecular Biology, Cambridge, United Kingdom.
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+/Gr-1+/ myeloid
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/Gr-1+ 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/Gr-1+ cells compared with wild-type tissues. Colony
replating, immunophenotyping, and cytochemistry suggest that any
perturbation of cellular differentiation from the prenatal stage onward
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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