Prenatal and postnatal myeloid cells demonstrate stepwise progression in the pathogenesis of MLL fusion gene leukemia.
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.
Johnson
Jennifer J
JJ
University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
Chen
Weili
W
Hudson
Wendy
W
Yao
Qing
Q
Taylor
Marnie
M
Rabbitts
Terence H
TH
Kersey
John H
JH
D000367:Age Factors; D000818:Animals; D001853:Bone Marrow / Q000196:embryology / Q000254:growth & development; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence; D003114:Colony-Forming Units Assay; D018450:Disease Progression; D004622:Embryo, Mammalian / Q000166:cytology; D005091:Exons / Q000235:genetics; D005260:Female; D018390:Gene Targeting; D005865:Gestational Age; D006413:Hematopoietic System / Q000196:embryology / Q000254:growth & development; D006801:Humans; D016130:Immunophenotyping; D007942:Leukemia, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D008099:Liver / Q000196:embryology / Q000254:growth & development; D008297:Male; D051379:Mice; D008954:Models, Biological; D016254:Mutagenesis, Insertional; D022423:Myeloid Cells / Q000473:pathology*; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D011828:Radiation Chimera; D013234:Stem Cells / Q000166:cytology
C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein