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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.

Original publication

DOI

10.1182/blood-2002-05-1515

Type

Journal article

Journal

Blood

Publication Date

15/04/2003

Volume

101

Pages

3229 - 3235

Keywords

Age Factors, Animals, Bone Marrow, Bone Marrow Transplantation, Cell Aging, Cell Transformation, Neoplastic, Colony-Forming Units Assay, Disease Progression, Embryo, Mammalian, Exons, Female, Gene Targeting, Gestational Age, Hematopoietic System, Humans, Immunophenotyping, Leukemia, Experimental, Liver, Male, Mice, Models, Biological, Mutagenesis, Insertional, Myeloid Cells, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Organ Specificity, Radiation Chimera, Stem Cells